8-hydroxyquinoline derivatives as diagnostic and therapeutic agents

ABSTRACT

The present application provides compounds useful in methods of treating neurological disorders such as Alzheimer&#39;s disease, and cancer such as prostate cancer. Also provided herein are radiolabeled compounds useful for imaging techniques, and techniques for diagnosis and monitoring of treatment of neurological disorders and cancer. An exemplary radiolabeled compound provided herein is useful as a radiotracer for positron emission tomography or single-photon emission computed tomography. Methods for preparing radiolabeled compounds and methods for preparing unlabeled compounds are also provided.

CLAIM OF PRIORITY

This application is a divisional application of U.S. patent applicationSer. No. 15/751,778, filed Feb. 9, 2018, which is a § 371 National StageApplication of PCT/US2016/017156, filed Feb. 9, 2016, which claimspriority to U.S. Provisional Patent Application Ser. No. 62/204,237,filed on Aug. 12, 2015, the entire contents of which are herebyincorporated by reference.

TECHNICAL FIELD

The present application relates to metal-chelating heterocycliccompounds, and more particularly to 8-hydroxyquinoline derivatives whichare useful for diagnosis and treatment of neurological disorders such asAlzheimer's disease, and cancers such as prostate cancer.

BACKGROUND

Alzheimer's disease (AD), a neurodegenerative disorder that affectsapproximately 44 million people world-wide, is the sixth leading causeof death with an estimated socioeconomic burden of more than $200billion. There is no cure for the debilitating disease with only fewsymptom-alleviating treatments. AD is characterized by extracellularamyloid plaques containing Cu and Zn, and which is accompanied byneuronal Cu deficiency and Zn dys-homeostasis. Zn and Cu ions areinvolved in the Aβ deposition and stabilization. Therefore, metalchelating agents may lead to the dissolution of Aβ deposits bypreventing metal-Aβ interaction.

Accordingly, there is a need for compounds that can act as metalchelators for modulating metal-Aβ interaction, and can be used to treatand diagnose neurological disorders such as Alzheimer's disease.Accordingly, the present application provides compounds useful in thetreatment of neurological disorders, in addition to methods of treatmentof such disorders, and diagnostic methods.

SUMMARY

The present application provides, inter alia, a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

Hal is selected from the group consisting of Cl, F, Br, and I;

n is 1, 2, or 3;

X is selected from the group consisting of O, S, S(O), S(O)₂, C(O), andNR^(N);

L¹ is selected from the group consisting of —C₁₋₆ alkylene-, —Y—C₁₋₆alkylene-, —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-, and —(O—C₁₋₄ alkylene)_(m)-,wherein m is an integer from 1 to 5, and wherein said alkylene groupsare each optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, CN, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃alkyl)amino;

L² is selected from the group consisting of —C₁₋₆ alkylene-, —C₁₋₆alkylene-Y—, —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-, and —(C₁₋₄alkylene-O—)_(m)—, wherein m is an integer from 1 to 5, and wherein saidalkylene groups are each optionally substituted with 1, 2, or 3substituents independently selected from halo, CN, OH, C₁₋₃ alkyl, C₁₋₃alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, anddi(C₁₋₃ alkyl)amino;

each Y is independently selected from the group consisting of O, S,S(O), S(O)₂, C(O), C(O)NR^(f), NR^(f)C(O), S(O)₂NR^(f), NR^(f)S(O)₂, andNR^(f);

each R^(f) is independently selected from the group consisting of H andC₁₋₃ alkyl;

R^(N) is selected from the group consisting of H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₃₋₁₀ cycloalkyl, and 4-10membered heterocycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₄ haloalkyl, C₃₋₁₀ cycloalkyl, and 4-10 memberedheterocycloalkyl are each optionally substituted by 1, 2, 3, or 4independently selected R^(g) groups;

group A is selected from the group consisting of a 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups;

alternatively, group A is H;

with the proviso that when X is NR^(N), L¹ is —C₁₋₆ alkylene-, L² is—C₁₋₆ alkylene-, and R^(N) is C₁₋₆ alkyl, group A is not H;

each R^(A) is independently selected from the group consisting of OH,NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino,C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino; and

each R^(g) is independently selected from the group consisting of OH,NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino,C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino.

In some embodiments, the compound of Formula I is a compound of FormulaIa:

or a pharmaceutically acceptable salt thereof, wherein:

Hal is selected from the group consisting of Cl, F, Br, and I;

X is selected from the group consisting of O, S, S(O), S(O)₂, C(O), andNR^(N);

L¹ is selected from the group consisting of —C₁₋₆ alkylene-, —Y—C₁₋₆alkylene-, —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-, or —(O—C₁₋₄ alkylene)_(m)-,wherein m is an integer from 1 to 5, and wherein said alkylene groupsare each optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, CN, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃alkyl)amino;

L² is selected from the group consisting of —C₁₋₆ alkylene-, —C₁₋₆alkylene-Y—, —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-, and —(C₁₋₄alkylene-O—)_(m)—, wherein m is an integer from 1 to 5, and wherein saidalkylene groups are each optionally substituted with 1, 2, or 3substituents independently selected from halo, CN, OH, C₁₋₃ alkyl, C₁₋₃alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, anddi(C₁₋₃ alkyl)amino;

each Y is independently selected from the group consisting of O, S,S(O), S(O)₂, C(O), C(O)NR^(f), NR^(f)C(O), S(O)₂NR^(f), NR^(f)S(O)₂, andNR^(f);

each R^(f) is independently selected from the group consisting of H andC₁₋₃ alkyl;

R^(N) is selected from the group consisting of H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₄ haloalkyl, C₃₋₁₀ cycloalkyl, and 4-10 membered heterocycloalkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(g) groups;

group A is selected from the group consisting of a 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups;

alternatively, group A is H;

with the proviso that when X is NR^(N), L¹ is —C₁₋₆ alkylene-, L² is—C₁₋₆ alkylene-, and R^(N) is C₁₋₆ alkyl, group A is not H;

each R^(A) is independently selected from the group consisting of OH,NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino,C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino; and

each R^(g) is independently selected from the group consisting of OH,NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino,C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino.

In some embodiments, Hal is selected from the group consisting of Cl, F,and I. In some embodiments, Hal is Cl.

In some embodiments, X is selected from the group consisting of O, S,and NR^(N).

In some embodiments, X is selected from the group consisting of O andNR^(N).

In some embodiments, X is selected from the group consisting of O and—N(C₁₋₆ alkyl)-.

In some embodiments, X is selected from the group consisting of O and—N(CH₃)—.

In some embodiments, L¹ is selected from the group consisting of —C₁₋₆alkylene-, —Y—C₁₋₆ alkylene-, and —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-,wherein said alkylene groups are each optionally substituted with 1, 2,or 3 substituents independently selected from halo, CN, OH, C₁₋₃ alkoxy,amino, C₁₋₃ alkylamino, and di(C₁₋₃ alkyl)amino.

In some embodiments, L¹ is selected from the group consisting of —C₁₋₆alkylene-, and —Y—C₁₋₆ alkylene-, wherein said alkylene groups are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, and amino.

In some embodiments, L¹ is —C₁₋₆ alkylene-, wherein said alkylene groupis optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, and amino;

In some embodiments, L¹ is methylene.

In some embodiments, L² is selected from the group consisting of —C₁₋₆alkylene-, —C₁₋₆ alkylene-Y—, and —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-,wherein said alkylene groups are each optionally substituted with 1, 2,or 3 substituents independently selected from halo, CN, OH, C₁₋₃ alkyl,C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,and di(C₁₋₃ alkyl)amino.

In some embodiments, L² is selected from the group consisting of —C₁₋₆alkylene- and —C₁₋₆ alkylene-Y—, wherein said alkylene groups are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, and amino.

In some embodiments, L² is —C₁₋₆ alkylene-, wherein said alkylene groupis optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, and amino.

In some embodiments, L² is selected from the group consisting ofmethylene, ethylene, and butylene.

In some embodiments, Y is selected from the group consisting of O, C(O),C(O)NR^(f), NR^(f)C(O), and NR^(f).

In some embodiments, Y is selected from the group consisting of O, C(O),—C(O)NH—, —NHC(O)—, NH, and —N(CH₃)—.

In some embodiments, R^(N) is selected from the group consisting of H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl.

In some embodiments, R^(N) is selected from the group consisting of Hand C₁₋₆ alkyl.

In some embodiments, R^(N) is —CH₃.

In some embodiments, X is selected from the group consisting of O, S,S(O), S(O)₂, and C(O); and group A is H.

In some embodiments, X is selected from the group consisting of O and S;and group A is H.

In some embodiments, X is O; and group A is H.

In some embodiments, L¹ is selected from the group consisting of —C₁₋₆alkylene-, and —Y—C₁₋₆ alkylene-, wherein said alkylene groups are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, and amino.

In some embodiments, L¹ is —C₁₋₆ alkylene-, wherein said alkylene groupis optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, and amino.

In some embodiments, L¹ is methylene.

In some embodiments, L² is —C₁₋₆ alkylene-, wherein said alkylene groupis optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃ alkylamino, anddi(C₁₋₃ alkyl)amino.

In some embodiments, L² is selected from the group consisting ofethylene and butylene, each of which is optionally substituted with 1,2, or 3 substituents independently selected from the group consisting ofhalo, CN, OH, C₁₋₃ alkoxy, amino, methylamino, and dimethylamino.

In some embodiments, L² is selected from the group consisting ofethylene and butylene, each of which is optionally substituted with 1,2, or 3 halogen substituents independently selected from Cl, F, and I.

In some embodiments, L² is selected from the group consisting ofethylene and butylene, each of which is optionally substituted with oneF.

In some embodiments, X is NR^(N); and group A is selected from the groupconsisting of a 5 or 6 membered heteroaryl and 4-10 memberedheterocycloalkyl, each of which is optionally substituted by 1, 2, 3, or4 independently selected R^(A) groups.

In some embodiments, X is NR^(N); and group A is a 5 or 6 memberedheteroaryl, which is optionally substituted by 1, 2, or 3 independentlyselected R^(A) groups.

In some embodiments, X is —N(C₁₋₆ alkyl)-; and group A is a 5 or 6membered heteroaryl, which is optionally substituted by 1, 2, or 3independently selected R^(A) groups.

In some embodiments, X is —N(C₁₋₆ alkyl)-; and group A is triazolyl,which is optionally substituted by 1, 2, or 3 independently selectedR^(A) groups.

In some embodiments, X is —N(CH₃)—; and group A is triazolyl, which isoptionally substituted by 1, 2, or 3 independently selected R^(A)groups.

In some embodiments, X is —N(CH₃)—; and group A is a triazolyl ofFormula A-1:

In some embodiments, L¹ is —C₁₋₆ alkylene-, wherein said alkylene groupis optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, and amino.

In some embodiments, L¹ is methylene.

In some embodiments, L² is —C₁₋₆ alkylene-, wherein said alkylene groupis optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃ alkylamino, anddi(C₁₋₃ alkyl)amino.

In some embodiments, L² is methylene.

In some embodiments, R^(A) is selected from the group consisting of OH,NO₂, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, and di(C₁₋₆alkyl)amino.

In some embodiments, R^(A) is selected from the group consisting ofhalo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, and di(C₁₋₆alkyl)amino.

In some embodiments, R^(A) is C₁₋₆ haloalkyl.

In some embodiments, R^(A) is selected from the group consisting of2-fluoroethyl, 3-fluoropropyl, and 4-fluorobutyl.

In some embodiments,

Hal is selected from the group consisting of Cl, F, and I;

X is selected from the group consisting of O, S, and NR^(N);

L¹ is selected from the group consisting of —C₁₋₆ alkylene-, —Y—C₁₋₆alkylene-, and —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-, wherein said alkylenegroups are each optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃alkylamino, and di(C₁₋₃ alkyl)amino;

L² is selected from the group consisting of —C₁₋₆ alkylene-, —C₁₋₆alkylene-Y—, and —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-, wherein said alkylenegroups are each optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, CN, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃alkyl)amino;

Y is selected from the group consisting of O, C(O), C(O)NR^(f),NR^(f)C(O), and NR^(f);

each R^(f) is independently selected from the group consisting of H andC₁₋₃ alkyl;

R^(N) is selected from the group consisting of H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, and C₁₋₄ haloalkyl;

group A is selected from the group consisting of a 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups;

alternatively, group A is H;

with the proviso that when X is NR^(N), L¹ is —C₁₋₆ alkylene-, L² is—C₁₋₆ alkylene-, and R^(N) is C₁₋₆ alkyl, group A is not H; and

each R^(A) is independently selected from the group consisting of OH,NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino,C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino.

In some embodiments,

Hal is Cl;

X is selected from the group consisting of O and NR^(N);

L¹ is —C₁₋₆ alkylene-, wherein said alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, and amino;

L² is —C₁₋₆ alkylene-, wherein said alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, and amino;

R^(N) is selected from the group consisting of H and C₁₋₆ alkyl;

group A is 5 or 6 membered heteroaryl, which is optionally substitutedby 1, 2, or 3 independently selected R^(A) groups;

alternatively, group A is H;

with the proviso that when X is NR^(N), L¹ is —C₁₋₆ alkylene-, L² is—C₁₋₆ alkylene-, and R^(N) is C₁₋₆ alkyl, group A is not H; and

each R^(A) is independently selected from the group consisting of OH,NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino,C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino

In some embodiments,

Hal is selected from the group consisting of Cl, F, and I;

X is selected from the group consisting of O, S, S(O), S(O)₂, and C(O);

L¹ is selected from the group consisting of —C₁₋₆ alkylene- and —Y—C₁₋₆alkylene-, wherein said alkylene groups are each optionally substitutedwith 1, 2, or 3 substituents independently selected from halo, CN, OH,C₁₋₃ alkoxy, and amino;

Y is selected from the group consisting of O, C(O), —C(O)NH—, —NHC(O)—,NH, and —N(CH₃)—;

L² is —C₁₋₆ alkylene-, wherein said alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃alkyl)amino;

group A is selected from the group consisting of a 5-6 memberedheteroaryl and 4-8 membered heterocycloalkyl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups; and

each R^(A) is independently selected from the group consisting of OH,NO₂, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, and di(C₁₋₆alkyl)amino.

In some embodiments,

Hal is selected from the group consisting of Cl, F, and I;

X is selected from the group consisting of O and S;

L¹ is —C₁₋₆ alkylene-, wherein said alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, and amino;

L² is —C₁₋₆ alkylene-, wherein said alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃alkyl)amino;

group A is 5-6 membered heteroaryl, which is optionally substituted by1, 2, or 3 independently selected R^(A) groups; and

each R^(A) is selected from the group consisting of halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, amino, C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino.

In some embodiments, the compound of Formula Ia is a compound of FormulaIb:

or a pharmaceutically acceptable salt thereof, wherein:

Hal is selected from the group consisting of Cl, F, and I; and

R⁰ is —C₁₋₆ alkyl, which is optionally substituted with 1, 2, or 3substituents independently selected from halo, CN, OH, C₁₋₃ alkoxy,amino, C₁₋₃ alkylamino, and di(C₁₋₃ alkyl)amino.

In some embodiments, R⁰ is C₁₋₆ haloalkyl.

In some embodiments, R⁰ is 2-fluoroethyl or 4-fluorobutyl.

In some embodiments,

Hal is selected from the group consisting of Cl, F, and I;

X is NR^(N);

L¹ is —C₁₋₆ alkylene-, wherein said alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, and amino;

L² is —C₁₋₆ alkylene-, wherein said alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃alkyl)amino;

R^(N) is selected from the group consisting of H and C₁₋₆ alkyl;

group A is selected from the group consisting of a 5 or 6 memberedheteroaryl and 4-10 membered heterocycloalkyl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups; and

R^(A) is selected from the group consisting of OH, NO₂, CN, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino.

In some embodiments,

Hal is selected from the group consisting of Cl, F, and I;

X is NR^(N);

L¹ is —C₁₋₃ alkylene-, wherein said alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, and amino;

L² is —C₁₋₃ alkylene-, wherein said alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃alkyl)amino;

R^(N) is selected from the group consisting of H and C₁₋₃ alkyl;

group A is 5 or 6 membered heteroaryl, which is optionally substitutedby 1, 2, or 3 independently selected R^(A) groups; and

R^(A) is selected from the group consisting of halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, amino, C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino.

In some embodiments, the compound of Formula Ia is a compound of FormulaIc:

or a pharmaceutically acceptable salt thereof, wherein:

Hal is selected from the group consisting of Cl, F, and I; and

group A is selected from the group consisting of a 5-6 memberedheteroaryl and 4-10 membered heterocycloalkyl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups.

In some embodiments, group A is a 5 membered heteroaryl, which isoptionally substituted by 1, 2, or 3 independently selected R^(A)groups.

In some embodiments, group A is triazolyl, which is optionallysubstituted by 1, 2, or 3 independently selected R^(A) groups.

In some embodiments, group A is a triazolyl of Formula A-1c:

In some embodiments, R^(A) is selected from the group consisting of OH,NO₂, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, and di(C₁₋₆alkyl)amino.

In some embodiments, R^(A) is selected from the group consisting of C₁₋₆alkyl, C₁₋₆ haloalkyl, cyano-C₁₋₃ alkyl, and HO—C₁₋₃ alkyl.

In some embodiments, R^(A) is C₁₋₆ haloalkyl.

In some embodiments, R^(A) is 2-fluoroethyl, 3-fluoropropyl, or4-fluorobutyl.

In some embodiments, the compound of Formula I is selected from thegroup consisting of:

or a pharmaceutically acceptable salt of any of the aforementioned.

In some embodiments, compound of Formula I is selected from the groupconsisting of:

or a pharmaceutically acceptable salt thereof.

The present application further provides a pharmaceutical compositioncomprising a compound of any one of Formulae I, Ia, Ib and Ic, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier.

The present application further provides a method of treating aneurological disorder in a subject in need thereof, the methodcomprising administering to the subject a therapeutically effectiveamount of a compound of any one of Formulae I, Ia, Ib and Ic, or apharmaceutically acceptable salt thereof.

In some embodiments, the neurological disorder comprises aneurodegenerative disease.

In some embodiments, the neurological disorder is a neurodegenerativedisease.

In some embodiments, neurodegenerative disease is selected from thegroup consisting of Alzheimer's disease (AD), Parkinson's disease (PD),Huntington's Disease (HD), motor neurone disease (MND), and Priondisease.

In some embodiments, neurodegenerative disease is Alzheimer's disease(AD).

In some embodiments, neurological disorder is selected from the groupconsisting of cerebral amyloid angiopathy, vascular cognitive impairment(VCI), dementia, dementia with Lewy bodies, frontotemporal dementia(FTD), amyotrophic lateral sclerosis (ALS), multiple sclerosis,hippocampal sclerosis, Binswanger's disease, and Creutzfeldt-Jakobdisease.

The present application further provides a method of treating cancer ina subject in need thereof, the method comprising administering to thesubject a therapeutically effective amount of a compound of Formulae I,Ia, Ib and Ic, or a pharmaceutically acceptable salt thereof

In some embodiments, the cancer is selected from the group consisting ofbladder cancer, brain cancer, breast cancer, colorectal cancer, cervicalcancer, gastrointestinal cancer, genitourinary cancer, head and neckcancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer,renal cancer, skin cancer, and testicular cancer.

In some embodiments, the cancer is prostate cancer.

The present application further provides a compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

Hal is selected from the group consisting of Cl, F, Br, and I;

n is 1, 2, or 3;

X is selected from the group consisting of O, S, S(O), S(O)₂, C(O), andNR^(N);

L¹ is selected from the group consisting of —C₁₋₆ alkylene-, —Y—C₁₋₆alkylene-, —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-, and —(O—C₁₋₄ alkylene)_(m)-,wherein m is an integer from 1 to 5, and wherein said alkylene groupsare each optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, CN, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃alkyl)amino;

L² is selected from the group consisting of —C₁₋₆ alkylene-, —C₁₋₆alkylene-Y—, —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-, and —(C₁₋₄alkylene-O—)_(m)—, wherein m is an integer from 1 to 5, and wherein saidalkylene groups are each optionally substituted with 1, 2, or 3substituents independently selected from halo, CN, OH, C₁₋₃ alkyl, C₁₋₃alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, anddi(C₁₋₃ alkyl)amino;

each Y is independently selected from the group consisting of O, S,S(O), S(O)₂, C(O), C(O)NR^(f), NR^(f)C(O), S(O)₂NR^(f), NR^(f)S(O)₂, andNR^(f);

each R^(f) is independently selected from the group consisting of H andC₁₋₃ alkyl;

R^(N) is selected from the group consisting of H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₃₋₁₀ cycloalkyl, and 4-10membered heterocycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₄ haloalkyl, C₃₋₁₀ cycloalkyl, and 4-10 memberedheterocycloalkyl are each optionally substituted by 1, 2, 3, or 4independently selected R^(g) groups;

group A is selected from the group consisting of a 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups;

alternatively, group A is H;

with the proviso that when X is NR^(N), L¹ is —C₁₋₆ alkylene-, L² is—C₁₋₆ alkylene-, and R^(N) is C₁₋₆ alkyl, group A is not H;

each R^(A) is independently selected from the group consisting of OH,NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino,C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino;

each R^(g) is independently selected from the group consisting of OH,NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino,C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino; and

wherein the compound of Formula (II) comprises at least oneradioisotope.

In some embodiments, the compound of Formula II is a compound of FormulaIIa:

or a pharmaceutically acceptable salt thereof, wherein:

Hal is selected from the group consisting of Cl, F, Br, and I;

X is selected from the group consisting of O, S, S(O), S(O)₂, C(O), andNR^(N);

L¹ is selected from the group consisting of —C₁₋₆ alkylene-, —Y—C₁₋₆alkylene-, —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-, and —(O—C₁₋₄ alkylene)_(m)-,wherein m is an integer from 1 to 5, and wherein said alkylene groupsare each optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, CN, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃alkyl)amino;

L² is selected from the group consisting of —C₁₋₆ alkylene-, —C₁₋₆alkylene-Y—, —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-, or —(C₁₋₄alkylene-O—)_(m)—, wherein m is an integer from 1 to 5, and wherein saidalkylene groups are each optionally substituted with 1, 2, or 3substituents independently selected from halo, CN, OH, C₁₋₃ alkyl, C₁₋₃alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, anddi(C₁₋₃ alkyl)amino;

each Y is independently selected from the group consisting of O, S,S(O), S(O)₂, C(O), C(O)NR^(f), NR^(f)C(O), S(O)₂NR^(f), NR^(f)S(O)₂, andNR^(f);

each R^(f) is independently selected from the group consisting of H andC₁₋₃ alkyl;

R^(N) is selected from the group consisting of H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₃₋₁₀ cycloalkyl, and 4-10membered heterocycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₄ haloalkyl, C₃₋₁₀ cycloalkyl, and 4-10 memberedheterocycloalkyl are each optionally substituted by 1, 2, 3, or 4independently selected R^(g) groups;

group A is selected from the group consisting of a 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups;

alternatively, group A is H;

with the proviso that when X is NR^(N), L¹ is —C₁₋₆ alkylene-, L² is—C₁₋₆ alkylene-, and R^(N) is C₁₋₆ alkyl, group A is not H;

each R^(A) is independently selected from the group consisting of OH,NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino,C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino;

each R^(g) is independently selected from the group consisting of OH,NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino,C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino; and

wherein the compound of Formula (IIa) comprises at least oneradioisotope.

In some embodiments, Hal is selected from the group consisting of Cl, F,and I. In some embodiments, Hal is Cl.

In some embodiments, X is selected from the group consisting of O, S,and NR^(N)

In some embodiments, X is selected from the group consisting of O andNR^(N).

In some embodiments, X is selected from the group consisting of O and—N(C₁₋₆ alkyl)-.

In some embodiments, X is selected from the group consisting of O and—N(CH₃)—.

In some embodiments, L¹ is selected from the group consisting of —C₁₋₆alkylene-, —Y—C₁₋₆ alkylene-, and —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-,wherein said alkylene groups are each optionally substituted with 1, 2,or 3 substituents independently selected from halo, CN, OH, C₁₋₃ alkoxy,amino, C₁₋₃ alkylamino, and di(C₁₋₃ alkyl)amino.

In some embodiments, L¹ is selected from the group consisting of —C₁₋₆alkylene-, and —Y—C₁₋₆ alkylene-, wherein said alkylene groups are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, and amino.

In some embodiments, L¹ is —C₁₋₆ alkylene-, wherein said alkylene groupis optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, and amino;

In some embodiments, L¹ is methylene.

In some embodiments, L² is selected from the group consisting of —C₁₋₆alkylene-, —C₁₋₆ alkylene-Y—, and —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-,wherein said alkylene groups are each optionally substituted with 1, 2,or 3 substituents independently selected from halo, CN, OH, C₁₋₃ alkyl,C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,and di(C₁₋₃ alkyl)amino.

In some embodiments, L² is selected from the group consisting of —C₁₋₆alkylene- and —C₁₋₆ alkylene-Y—, wherein said alkylene groups are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, and amino.

In some embodiments, L² is —C₁₋₆ alkylene-, wherein said alkylene groupis optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, and amino.

In some embodiments, L² is selected from the group consisting ofmethylene, ethylene, and butylene.

In some embodiments, Y is selected from the group consisting of O, C(O),C(O)NR^(f), NR^(f)C(O), and NR^(f).

In some embodiments, Y is selected from the group consisting of O, C(O),—C(O)NH—, —NHC(O)—, NH, and —N(CH₃)—.

In some embodiments, R^(N) is selected from the group consisting of H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₄ haloalkyl.

In some embodiments, R^(N) is selected from the group consisting of Hand C₁₋₆ alkyl.

In some embodiments, R^(N) is —CH₃.

In some embodiments, X is selected from the group consisting of O, S,S(O), S(O)₂, and C(O); and group A is H.

In some embodiments, X is selected from the group consisting of O and S;and group A is H.

In some embodiments, X is O; and group A is H.

In some embodiments, L¹ is selected from the group consisting of —C₁₋₆alkylene-, and —Y—C₁₋₆ alkylene-, wherein said alkylene groups are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, and amino.

In some embodiments, L¹ is —C₁₋₆ alkylene-, wherein said alkylene groupis optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, and amino.

In some embodiments, L¹ is methylene.

In some embodiments, L² is —C₁₋₆ alkylene-, wherein said alkylene groupis optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃ alkylamino, anddi(C₁₋₃ alkyl)amino.

In some embodiments, L² is selected from the group consisting ofethylene and butylene, each of which is optionally substituted with 1,2, or 3 substituents independently selected from the group consisting ofhalo, CN, OH, C₁₋₃ alkoxy, amino, methylamino, and dimethylamino.

In some embodiments, L² is selected from the group consisting ofethylene and butylene, each of which is optionally substituted with 1,2, or 3 halogen substituents independently selected from Cl, F, and I.

In some embodiments, L² is selected from the group consisting ofethylene and butylene, each of which is optionally substituted with oneF.

In some embodiments, X is NR^(N); and group A is selected from the groupconsisting of a 5 or 6 membered heteroaryl and 4-10 memberedheterocycloalkyl, each of which is optionally substituted by 1, 2, 3, or4 independently selected R^(A) groups.

In some embodiments, X is NR^(N); and group A is a 5 or 6 memberedheteroaryl, which is optionally substituted by 1, 2, or 3 independentlyselected R^(A) groups.

In some embodiments, X is —N(C₁₋₆ alkyl)-; and group A is triazolyl,which is optionally substituted by 1, 2, or 3 independently selectedR^(A) groups.

In some embodiments, X is —N(CH₃)—; and group A is triazolyl, which isoptionally substituted by 1, 2, or 3 independently selected R^(A)groups.

In some embodiments, X is —N(CH₃)—; and group A is a triazolyl ofFormula A-1:

In some embodiments, L¹ is —C₁₋₆ alkylene-, wherein said alkylene groupis optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, and amino.

In some embodiments, L¹ is methylene.

In some embodiments, L² is —C₁₋₆ alkylene-, wherein said alkylene groupis optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃ alkylamino, anddi(C₁₋₃ alkyl)amino.

In some embodiments, L² is methylene.

In some embodiments, R^(A) is selected from the group consisting of OH,NO₂, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, and di(C₁₋₆alkyl)amino.

In some embodiments, R^(A) is selected from the group consisting ofhalo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, and di(C₁₋₆alkyl)amino.

In some embodiments, R^(A) is C₁₋₆ haloalkyl.

In some embodiments, R^(A) is 2-fluoroethyl, 3-fluoropropyl, or4-fluorobutyl.

In some embodiments,

Hal is selected from the group consisting of Cl, F, and I;

X is selected from the group consisting of O, S, and NR^(N);

L¹ is selected from the group consisting of —C₁₋₆ alkylene-, —Y—C₁₋₆alkylene-, and —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-, wherein said alkylenegroups are each optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃alkylamino, and di(C₁₋₃ alkyl)amino;

L² is selected from the group consisting of —C₁₋₆ alkylene-, —C₁₋₆alkylene-Y—, and —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-, wherein said alkylenegroups are each optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, CN, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃alkyl)amino;

Y is selected from the group consisting of O, C(O), C(O)NR^(f),NR^(f)C(O), and NR^(f);

each R^(f) is independently selected from the group consisting of H andC₁₋₃ alkyl;

R^(N) is selected from the group consisting of H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl;

group A is selected from the group consisting of a 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups;

alternatively, group A is H;

with the proviso that when X is NR^(N), L¹ is —C₁₋₆ alkylene-, L² is—C₁₋₆ alkylene-, and R^(N) is C₁₋₆ alkyl, group A is not H; and

each R^(A) is independently selected from the group consisting of OH,NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino,C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino.

In some embodiments,

Hal is Cl;

X is selected from the group consisting of O and NR^(N);

L¹ is —C₁₋₆ alkylene-, wherein said alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, and amino;

L² is —C₁₋₆ alkylene-, wherein said alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, and amino;

R^(N) is selected from the group consisting of H and C₁₋₆ alkyl;

group A is 5 or 6 membered heteroaryl, which is optionally substitutedby 1, 2, or 3 independently selected R^(A) groups;

alternatively, group A is H;

with the proviso that when X is NR^(N), L¹ is —C₁₋₆ alkylene-, L² is—C₁₋₆ alkylene-, and R^(N) is C₁₋₆ alkyl, group A is not H; and

each R^(A) is independently selected from the group consisting of OH,NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino,C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino.

In some embodiments,

Hal is selected from the group consisting of Cl, F, and I;

X is selected from the group consisting of O, S, S(O), S(O)₂, and C(O);

L¹ is selected from the group consisting of —C₁₋₆ alkylene-, and —Y—C₁₋₆alkylene-, wherein said alkylene groups are each optionally substitutedwith 1, 2, or 3 substituents independently selected from halo, CN, OH,C₁₋₃ alkoxy, and amino;

Y is selected from the group consisting of O, C(O), —C(O)NH—, —NHC(O)—,NH, and —N(CH₃)—;

L² is —C₁₋₆ alkylene-, wherein said alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃alkyl)amino;

group A is selected from the group consisting of a 5-6 memberedheteroaryl and 4-8 membered heterocycloalkyl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups; and

each R^(A) is independently selected from the group consisting of OH,NO₂, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, and di(C₁₋₆alkyl)amino.

In some embodiments,

Hal is selected from the group consisting of Cl, F, and I;

X is selected from the group consisting of O and S;

L¹ is —C₁₋₆ alkylene-, wherein said alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, and amino;

L² is —C₁₋₆ alkylene-, wherein said alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃alkyl)amino;

group A is 5-6 membered heteroaryl, which is optionally substituted by1, 2, or 3 independently selected R^(A) groups; and

each R^(A) is selected from the group consisting of halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, amino, C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino.

In some embodiments, the compound of Formula IIa is a compound ofFormula IIb:

or a pharmaceutically acceptable salt thereof, wherein:

Hal is selected from the group consisting of Cl, F, and I; and

R⁰ is —C₁₋₆ alkyl, which is optionally substituted with 1, 2, or 3substituents independently selected from halo, CN, OH, C₁₋₃ alkoxy,amino, C₁₋₃ alkylamino, and di(C₁₋₃ alkyl)amino;

wherein the compound of Formula (IIb) comprises at least oneradioisotope.

In some embodiments, R⁰ is C₁₋₆ haloalkyl.

In some embodiments, R⁰ is 2-fluoroethyl or 4-fluorobutyl.

In some embodiments, R⁰ comprises at least one radioisotope.

In some embodiments, R⁰ comprises one radioisotope.

In some embodiments,

Hal is selected from the group consisting of Cl, F, and I;

X is NR^(N);

L¹ is —C₁₋₆ alkylene-, wherein said alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, and amino;

L² is —C₁₋₆ alkylene-, wherein said alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃alkyl)amino;

R^(N) is selected from the group consisting of H and C₁₋₆ alkyl;

group A is selected from the group consisting of a 5 or 6 memberedheteroaryl and 4-10 membered heterocycloalkyl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups; and

R^(A) is selected from the group consisting of OH, NO₂, CN, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino.

In some embodiments,

Hal is selected from the group consisting of Cl, F, and I;

X is NR^(N);

L¹ is —C₁₋₃ alkylene-, wherein said alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, and amino;

L² is —C₁₋₃ alkylene-, wherein said alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃alkyl)amino;

R^(N) is selected from the group consisting of H and C₁₋₃ alkyl;

group A is 5 or 6 membered heteroaryl, which is optionally substitutedby 1, 2, or 3 independently selected R^(A) groups; and

R^(A) is selected from the group consisting of halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, amino, C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino.

In some embodiments, the compound of Formula IIa is a compound ofFormula IIc:

or a pharmaceutically acceptable salt thereof, wherein:

Hal is selected from the group consisting of Cl, F, and I;

group A is selected from the group consisting of a 5-6 memberedheteroaryl and 4-10 membered heterocycloalkyl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups; and

wherein the compound of Formula (IIc) comprises at least oneradioisotope.

In some embodiments, group A is a 5 membered heteroaryl, which isoptionally substituted by 1, 2, or 3 independently selected R^(A)groups.

In some embodiments, group A is triazolyl, which is optionallysubstituted by 1, 2, or 3 independently selected R^(A) groups.

In some embodiments, group A is a triazolyl of Formula A-1c:

In some embodiments, R^(A) is selected from the group consisting of OH,NO₂, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, and di(C₁₋₆alkyl)amino.

In some embodiments, R^(A) is selected from the group consisting of C₁₋₆alkyl, C₁₋₆ haloalkyl, cyano-C₁₋₃ alkyl, and HO—C₁₋₃ alkyl.

In some embodiments, R^(A) is C₁₋₆ haloalkyl.

In some embodiments, R^(A) is 2-fluoroethyl, 3-fluoropropyl, or4-fluorobutyl.

In some embodiments, R^(A) comprises at least one radioisotope.

In some embodiments, R^(A) comprises one radioisotope.

In some embodiments, R^(N) comprises at least one radioisotope.

In some embodiments, R^(N) comprises one radioisotope.

In some embodiments, L² comprises at least one radioisotope.

In some embodiments, L² comprises one radioisotope.

In some embodiments, at least one Hal is a radioisotope.

In some embodiments, one Hal is a radioisotope.

In some embodiments, the at least one radioisotope is a positronemitter.

In some embodiments, the positron emitter is selected from the groupconsisting of ¹¹C, ¹³N, ¹⁵O, ¹⁸F, ^(34m)Cl, ³⁸K, ⁴⁵Ti, ⁵¹Mn, ^(52m)Mn,⁵²Fe, ⁵⁵Co, ⁶⁰Cu, ⁶¹Cu, ⁶²Cu, ⁶⁴Cu, ⁶⁶Ga, ⁶⁸Ga, ⁷¹As, ⁷²As, ⁷⁴As, ⁷⁵Br,⁷⁶Br, ⁸²Rb, ⁸⁶Y, ⁸⁹Zr, ⁹⁰Nb, ^(94m)Tc, ^(110m)In, ¹¹⁸Sb, ¹²⁰I, ¹²¹I,¹²²I, and ¹²⁴I.

In some embodiments, the positron emitter is ¹¹C or ¹⁸F.

In some embodiments, the at least one radioisotope is a gamma emitter.

In some embodiments, the gamma emitter is selected from the groupconsisting of ^(99m)Tc, ¹²³I, ¹²⁵I ¹³¹I and ¹²³I.

In some embodiments, the compound comprises one radioisotope.

In some embodiments, the compound of Formula II is selected from thegroup consisting of:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula II is selected from thegroup consisting of:

or a pharmaceutically acceptable salt thereof.

The present application further provides a pharmaceutical compositioncomprising a compound of any one of Formulae II, IIa, IIb, and IIc, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier.

The present application further provides a method of imaging the brainof a subject, the method comprising:

-   -   i. administering to the subject an effective amount of a        compound of any one of Formulae II, IIa, IIb, and IIc, or a        pharmaceutically acceptable salt thereof,    -   ii. waiting a time sufficient to allow the compound to        accumulate in the brain to be imaged; and    -   iii. imaging the brain with an imaging technique.

The present application further provides a method of diagnosing aneurological disorder in a subject, the method comprising:

-   -   i. administering to the subject a compound of any one of        Formulae II, IIa, IIb, and IIc;    -   ii. waiting a time sufficient to allow the compound to        accumulate at a tissue or cell site associated with the        neurological disorder; and    -   iii. imaging the cell or tissue with an imaging technique.

The present application further provides a method of monitoringtreatment of a neurological disorder in a subject, the methodcomprising:

-   -   i. imaging a cell or tissue with an imaging technique;    -   ii. administering to the subject a compound of any one of        Formulae II, IIa, IIb, and IIc in an effective amount of to        treat the neurological disorder;    -   iii. waiting a time sufficient to allow the compound to        accumulate at a tissue or cell site associated with the        neurological disorder;    -   iv. imaging the cell or tissue with an imaging technique; and    -   v. comparing the image of step i) and the image of step iv).

In some embodiments, the imaging technique is selected from the groupconsisting of magnetic resonance imaging, optical imaging, single-photonemission computer tomography, positron emission tomography imaging,positron emission tomography with computer tomography imaging, andpositron emission tomography with magnetic resonance imaging.

In some embodiments, the imaging technique is selected from the groupconsisting of positron emission tomography (PET) and single-photonemission computer tomography (SPECT).

In some embodiments, the neurological disorder comprises aneurodegenerative disease.

In some embodiments, the neurological disorder is a neurodegenerativedisease.

In some embodiments, neurodegenerative disease is selected from thegroup consisting of Alzheimer's disease (AD), Parkinson's disease (PD),Huntington's Disease (HD), motor neurone disease (MND), and Priondisease.

In some embodiments, neurodegenerative disease is Alzheimer's disease(AD).

In some embodiments, neurological disorder is selected from the groupconsisting of cerebral amyloid angiopathy, vascular cognitive impairment(VCI), dementia, dementia with Lewy bodies, frontotemporal dementia(FTD), amyotrophic lateral sclerosis (ALS), multiple sclerosis,hippocampal sclerosis, Binswanger's disease, and Creutzfeldt-Jakobdisease.

The present application further provides a method of diagnosing a cancerin a subject, the method comprising:

-   -   i. administering to the subject a compound of any one of        Formulae II, IIa, IIb;    -   ii. waiting a time sufficient to allow the compound to        accumulate at a tissue or cell site associated with the cancer;        and    -   iii. imaging the cell or tissue with an imaging technique.

The present application further provides a method of monitoringtreatment of a cancer in a subject, the method comprising:

-   -   i. imaging a cell or tissue with an imaging technique;    -   ii. administering to the subject a compound of any one of        Formulae II, IIa, IIb in an effective amount of to treat the        cancer;    -   iii. waiting a time sufficient to allow the compound to        accumulate at a tissue or cell site associated with the cancer;    -   iv. imaging the cell or tissue with an imaging technique; and    -   v. comparing the image of step i) and the image of step iv).

In some embodiments, the imaging technique is selected from the groupconsisting of magnetic resonance imaging, optical imaging, single-photonemission computer tomography, positron emission tomography imaging,positron emission tomography with computer tomography imaging, andpositron emission tomography with magnetic resonance imaging.

In some embodiments, the imaging technique is selected from the groupconsisting of positron emission tomography (PET) and single-photonemission computer tomography (SPECT).

In some embodiments, the cancer is selected from the group consisting ofbladder cancer, brain cancer, breast cancer, colorectal cancer, cervicalcancer, gastrointestinal cancer, genitourinary cancer, head and neckcancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer,renal cancer, skin cancer, and testicular cancer.

In some embodiments, the cancer is prostate cancer.

The present application further provides a compound of Formula III:

or a pharmaceutically acceptable salt thereof, wherein:

each X¹ and X² is independently selected from the group consisting of F,Cl, Br, and I;

wherein at least one of X¹ and X² comprises a radioisotope; and

wherein:

when X¹ is I or F, then X² is not Cl; and

when X¹ is I, then X² is not F.

In some embodiments, X¹ is F and X² is Br.

In some embodiments, X¹ is F and X² is I.

In some embodiments, X¹ is Cl and X² is F.

In some embodiments, X¹ is Br and X² is F.

In some embodiments, X¹ is F and X² is F.

In some embodiments, X¹ is I and X² is Br.

In some embodiments, the compound of Formula III is selected from thegroup consisting of:

or a pharmaceutically acceptable salt thereof.

The present application further provides a pharmaceutical compositioncomprising a compound of any one of Formula III, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier.

The present application further provides a method of imaging the brainof a subject, the method comprising:

-   -   i. administering to the subject an effective amount of a        compound of any one of Formula III, or a pharmaceutically        acceptable salt thereof;    -   ii. waiting a time sufficient to allow the compound to        accumulate the brain to be imaged; and    -   iii. imaging the brain with an imaging technique.

The present application further provides a method of diagnosing aneurological disorder in a subject, the method comprising:

-   -   i. administering to the subject a compound of any one of Formula        III;    -   ii. waiting a time sufficient to allow the compound to        accumulate at a tissue or cell site associated with the        neurological disorder; and    -   iii. imaging the cell or tissue with an imaging technique.

The present application further provides a method of monitoringtreatment of a neurological disorder in a subject, the methodcomprising:

-   -   i. imaging a cell or tissue with an imaging technique;    -   ii. administering to the subject a compound of any one of        Formula III in an effective amount of to treat the neurological        disorder;    -   iii. waiting a time sufficient to allow the compound to        accumulate at a tissue or cell site associated with the        neurological disorder;    -   iv. imaging the cell or tissue with an imaging technique; and    -   v. comparing the image of step i) and the image of step iv).

In some embodiments, the imaging technique is selected from the groupconsisting of magnetic resonance imaging, optical imaging, single-photonemission computer tomography, positron emission tomography imaging,positron emission tomography with computer tomography imaging, andpositron emission tomography with magnetic resonance imaging.

In some embodiments, the imaging technique is selected from the groupconsisting of positron emission tomography (PET) and single-photonemission computer tomography (SPECT).

In some embodiments, the neurological disorder comprises aneurodegenerative disease.

In some embodiments, the neurological disorder is a neurodegenerativedisease.

In some embodiments, neurodegenerative disease is selected from thegroup consisting of Alzheimer's disease (AD), Parkinson's disease (PD),Huntington's Disease (HD), motor neurone disease (MND), and Priondisease.

In some embodiments, neurodegenerative disease is Alzheimer's disease(AD).

In some embodiments, neurological disorder is selected from the groupconsisting of cerebral amyloid angiopathy, vascular cognitive impairment(VCI), dementia, dementia with Lewy bodies, frontotemporal dementia(FTD), amyotrophic lateral sclerosis (ALS), multiple sclerosis,hippocampal sclerosis, Binswanger's disease, and Creutzfeldt-Jakobdisease.

The present application further provides a method of diagnosing a cancerin a subject, the method comprising:

-   -   i. administering to the subject a compound of any one of Formula        III;    -   ii. waiting a time sufficient to allow the compound to        accumulate at a tissue or cell site associated with the cancer;        and    -   iii. imaging the cell or tissue with an imaging technique.

The present application further provides a method of monitoringtreatment of a cancer in a subject, the method comprising:

-   -   i. imaging a cell or tissue with an imaging technique;    -   ii. administering to the subject a compound of any one of        Formula III in an effective amount of to treat the cancer;    -   iii. waiting a time sufficient to allow the compound to        accumulate at a tissue or cell site associated with the cancer;    -   iv. imaging the cell or tissue with an imaging technique; and    -   v. comparing the image of step i) and the image of step iv).

In some embodiments, the imaging technique is selected from the groupconsisting of magnetic resonance imaging, optical imaging, single-photonemission computer tomography, positron emission tomography imaging,positron emission tomography with computer tomography imaging, andpositron emission tomography with magnetic resonance imaging.

In some embodiments, the imaging technique is selected from the groupconsisting of positron emission tomography (PET) and single-photonemission computer tomography (SPECT).

In some embodiments, the cancer is selected from the group consisting ofbladder cancer, brain cancer, breast cancer, colorectal cancer, cervicalcancer, gastrointestinal cancer, genitourinary cancer, head and neckcancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer,renal cancer, skin cancer, and testicular cancer.

In some embodiments, the cancer is prostate cancer.

DESCRIPTION OF DRAWINGS

FIG. 1 shows an ionophore assay of 8HQ and 8HQ derivatives: Compounds2-10.

FIG. 2 shows an ionophore activity of 8HQ derivatives: Compounds 12-17.

FIG. 3 shows an ionophore activity of 8HQ derivatives: Compounds 23, 24,28-30.

DETAILED DESCRIPTION

A metal-chelating agent, 5-chloro-7-iodo-quinolin-8-ol (clioquinol; CQ),has been shown to prevent Aβ toxicity. CQ not only prevents or reversesextracellular Aβ aggregation, but also transports metal ions as membranepenetrating metal complexes to increase intracellular metalconcentration, thereby initiating protective cell signaling events todegrade Aβ and prevent toxicity. In a pilot phase II clinical trial, CQwas well tolerated and attenuated the rate of cognitive decline in ADpatients, however further development was halted due to a contaminantduring the manufacturing process. Another metal chelator, PBT2(5,7-Dichloro-2-((dimethylamino)methyl) 8-quinolinol) has shown benefitsin patients with Huntington's disease and patients with AD in phase IIclinical trials.

To identify a suitable metal chelator for AD drug development, aradiopharmaceutical based on a metal chelator would be useful todetermine metal concentration and distribution in the living brain bypositron emission tomography (PET) or single-photon emission computedtomography (SPECT). Development of such agents could advance theunderstanding of AD etiology that is affected by dysregulation of metalfunctions, and could prove useful in monitoring therapeutic response anddisease progression for patients with AD.

Accordingly, the present application provides a series of8-hydroxyquinoline derivatives and identifies several potent and metalselective chelators for therapeutic applications that are also amenablefor labeling with radionuclides such as ¹⁸F and/or ¹¹C as potential PETligands or with ¹²³I as potential SPECT ligands. The present applicationdescribes compounds that showed superior binding affinity, metalselectivity, and Cu and Zn ionophore activity over the agents CQ andPBT2. The compounds of the present application are useful as drugcandidates and/or as PET or SPECT ligands to diagnose and/or treatneurological disorders such as Alzheimer's disease.

Compounds

The present application provides, inter alia, a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

Hal is selected from the group consisting of Cl, F, Br, and I;

n is 1, 2, or 3;

X is selected from the group consisting of O, S, S(O), S(O)₂, C(O), andNR^(N);

L¹ is selected from the group consisting of —C₁₋₆ alkylene-, —Y—C₁₋₆alkylene-, —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-, and —(O—C₁₋₄ alkylene)_(m)-,wherein m is an integer from 1 to 5, and wherein the alkylene groups areeach optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl,C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃ alkyl)amino;

L² is selected from the group consisting of —C₁₋₆ alkylene-, —C₁₋₆alkylene-Y—, —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-, and —(C₁₋₄alkylene-O—)_(m)—, wherein m is an integer from 1 to 5, and wherein thealkylene groups are each optionally substituted with 1, 2, or 3substituents independently selected from halo, CN, OH, C₁₋₃ alkyl, C₁₋₃alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, anddi(C₁₋₃ alkyl)amino;

each Y is independently selected from the group consisting of O, S,S(O), S(O)₂, C(O), C(O)NR^(f), NR^(f)C(O), S(O)₂NR^(f), NR^(f)S(O)₂, andNR^(f);

each R^(f) is independently selected from the group consisting of H andC₁₋₃ alkyl;

R^(N) is selected from the group consisting of H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₃₋₁₀ cycloalkyl, and 4-10membered heterocycloalkyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₄ haloalkyl, C₃₋₁₀ cycloalkyl, and 4-10 memberedheterocycloalkyl are each optionally substituted by 1, 2, 3, or 4independently selected R⁹ groups; group A is selected from the groupconsisting of a 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl, each of which is optionally substituted by 1, 2, 3, or4 independently selected R^(A) groups;

alternatively, group A is H;

with the proviso that when X is NR^(N), L¹ is —C₁₋₆ alkylene-, L² is—C₁₋₆ alkylene-, and R^(N) is C₁₋₆ alkyl, group A is not H;

each R^(A) is independently selected from the group consisting of OH,NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino,C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino; and

each R^(g) is independently selected from the group consisting of OH,NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino,C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino.

In some embodiments, Hal is selected from the group consisting of Cl, F,and I. In some embodiments, Hal is Cl. In some embodiments, Hal is F. Insome embodiments, Hal is I. In some embodiments, both Hal groups are Cl.In some embodiments, both Hal groups are F. In some embodiments, bothHal groups are I. In some embodiments, one of the Hal groups is Cl andanother Hal group is F. In some embodiments, one of the Hal groups is Cland another Hal group is I. In some embodiments, one of the Hal groupsis F and another Hal group is I.

In some embodiments, X is selected from the group consisting of O, S,and NR^(N). In some embodiments, X is selected from the group consistingof O and NR^(N). In some embodiments, X is selected from the groupconsisting of O and —N(C₁₋₆ alkyl)-. In some embodiments, X is selectedfrom the group consisting of O and —N(CH₃)—. In some embodiments, X isO. In some embodiments, X is NR^(N). In some embodiments, —N(C₁₋₆alkyl)-. In some embodiments, —N(CH₃)—.

In some embodiments, L¹ is selected from the group consisting of —C₁₋₆alkylene-, —Y—C₁₋₆ alkylene-, and —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-,wherein the alkylene groups are each optionally substituted with 1, 2,or 3 substituents independently selected from halo, CN, OH, C₁₋₃ alkoxy,amino, C₁₋₃ alkylamino, and di(C₁₋₃ alkyl)amino.

In some embodiments, L¹ is selected from the group consisting of —C₁₋₆alkylene-, and —Y—C₁₋₆ alkylene-, wherein the alkylene groups are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, and amino.

In some embodiments, L¹ is —C₁₋₆ alkylene-, wherein the alkylene groupis optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, and amino. In some embodiments,L¹ is methylene.

In some embodiments, L² is selected from the group consisting of —C₁₋₆alkylene-, —C₁₋₆ alkylene-Y—, and —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-,wherein the alkylene groups are each optionally substituted with 1, 2,or 3 substituents independently selected from halo, CN, OH, C₁₋₃ alkyl,C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,and di(C₁₋₃ alkyl)amino.

In some embodiments, L² is selected from the group consisting of —C₁₋₆alkylene- and —C₁₋₆ alkylene-Y—, wherein the alkylene groups are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, and amino.

In some embodiments, L² is —C₁₋₆ alkylene-, wherein the alkylene groupis optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, and amino. In some embodiments,L² is selected from the group consisting of methylene, ethylene, andbutylene.

In some embodiments, Y is selected from the group consisting of O, C(O),C(O)NR^(f), NR^(f)C(O), and NR. In some embodiments, Y is selected fromthe group consisting of O, C(O), —C(O)NH—, —NHC(O)—, NH, and —N(CH₃)—.

In some embodiments, R^(N) is selected from the group consisting of H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl. In someembodiments, R^(N) is selected from the group consisting of H and C₁₋₆alkyl. In some embodiments, R^(N) is H. In some embodiments, R^(N) isC₁₋₆ alkyl. In some embodiments, R^(N) is C₁₋₄ haloalkyl. In someembodiments, R^(N) is —CH₃.

In some embodiments, X is selected from the group consisting of O, S,S(O), S(O)₂, and C(O); and group A is H. In some embodiments, X isselected from the group consisting of O and S; and group A is H. In someembodiments, X is O; and group A is H. In some aspects of theseembodiments, L¹ is selected from the group consisting of —C₁₋₆alkylene-, and —Y—C₁₋₆ alkylene-, wherein the alkylene groups are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, and amino. In some aspects ofthese embodiments, L¹ is —C₁₋₆ alkylene-, wherein the alkylene group isoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, and amino. In some aspects ofthese embodiments, L¹ is methylene. In some aspects of theseembodiments, L² is —C₁₋₆ alkylene-, wherein the alkylene group isoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃ alkylamino, anddi(C₁₋₃ alkyl)amino. In some aspects of these embodiments, L² isselected from the group consisting of ethylene and butylene, each ofwhich is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halo, CN, OH, C₁₋₃alkoxy, amino, methylamino, and dimethylamino. In some aspects of theseembodiments, L² is selected from the group consisting of ethylene andbutylene, each of which is optionally substituted with 1, 2, or 3halogen substituents independently selected from Cl, F, and I. In someaspects of these embodiments, L² is selected from the group consistingof ethylene and butylene, each of which is optionally substituted withone F. In some aspects of these embodiments, L² is fluoroethylene. Insome aspects of these embodiments, L² is fluorobutylene.

In some embodiments, X is NR^(N); and group A is selected from the groupconsisting of a 5 or 6 membered heteroaryl and 4-10 memberedheterocycloalkyl, each of which is optionally substituted by 1, 2, 3, or4 independently selected R^(A) groups. In some embodiments, X is NR^(N);and group A is a 5 or 6 membered heteroaryl, which is optionallysubstituted by 1, 2, or 3 independently selected R^(A) groups. In someembodiments, X is —N(C₁₋₆ alkyl)-; and group A is a 5 or 6 memberedheteroaryl, which is optionally substituted by 1, 2, or 3 independentlyselected R^(A) groups. In some embodiments, X is —N(C₁₋₆ alkyl)-; andgroup A is triazolyl, which is optionally substituted by 1, 2, or 3independently selected R^(A) groups. In some embodiments, X is —N(CH₃)—;and group A is triazolyl, which is optionally substituted by 1, 2, or 3independently selected R^(A) groups. In some embodiments, X is —N(CH₃)—;and group A is a triazolyl of Formula A-1:

In some aspects of these embodiments, L¹ is —C₁₋₆ alkylene-, wherein thealkylene group is optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, CN, OH, C₁₋₃ alkoxy, and amino. Insome aspects of these embodiments, L¹ is methylene. In some aspects ofthese embodiments, L² is —C₁₋₆ alkylene-, wherein the alkylene group isoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃ alkylamino, anddi(C₁₋₃ alkyl)amino. In some aspects of these embodiments, L² ismethylene. In some aspects of these embodiments, R^(A) is selected fromthe group consisting of OH, NO₂, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino,C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino. In some aspects of theseembodiments, R^(A) is selected from the group consisting of halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino. In someaspects of these embodiments, R^(A) is C₁₋₆ haloalkyl. In some aspectsof these embodiments, R^(A) is selected from the group consisting of2-fluoroethyl, 3-fluoropropyl, and 4-fluorobutyl. In some aspects ofthese embodiments, R^(A) is 2-fluoroethyl. In some aspects of theseembodiments, R^(A) is 3-fluoropropyl. In some aspects of theseembodiments, R^(A) is 4-fluorobutyl.

In some embodiments, group A is H.

In some embodiments, group A is selected from the group consisting of a5 or 6 membered heteroaryl and 4-10 membered heterocycloalkyl, each ofwhich is optionally substituted by 1, 2, 3, or 4 independently selectedR^(A) groups.

In some embodiments, group A is 5 or 6 membered heteroaryl which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups. In some embodiments, group A is 5 membered heteroaryl which isoptionally substituted by 1, 2, or 3 independently selected R^(A)groups. In some embodiments, group A is 6 membered heteroaryl which isoptionally substituted by 1, 2, or 3 independently selected R^(A)groups.

In some embodiments, group A is selected from the group consisting ofpyridinyl, triazinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, each ofwhich is optionally substituted by 1, 2, 3, or 4 independently selectedR^(A) groups. In some embodiments, group A is selected from the groupconsisting of triazolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl,isothiazolyl, thiazolyl, furanyl, and thiophenyl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups.

In some embodiments, group A is triazolyl, which is optionallysubstituted by 1, 2, 3, or 4 independently selected R^(A) groups. Insome embodiments, group A is triazolyl, which is optionally substitutedby 1 R^(A) group.

In some embodiments, group A is a triazolyl of Formula A-1:

In some embodiments, group A is 4-10 membered heterocycloalkyl, which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups

In some embodiments, R^(A) is C₁₋₆ haloalkyl. In some embodiments, R^(A)is selected from the group consisting of 2-fluoroethyl, 3-fluoropropyl,and 4-fluorobutyl. In some embodiments, R^(A) is 2-fluoroethyl. In someembodiments, R^(A) is 3-fluoropropyl. In some embodiments, R^(A) is4-fluorobutyl.

In some embodiments,

Hal is selected from the group consisting of Cl, F, and I;

X is selected from the group consisting of O, S, and NR^(N);

L¹ is selected from the group consisting of —C₁₋₆ alkylene-, —Y—C₁₋₆alkylene-, and —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-, wherein the alkylenegroups are each optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃alkylamino, and di(C₁₋₃ alkyl)amino;

L² is selected from the group consisting of —C₁₋₆ alkylene-, —C₁₋₆alkylene-Y—, and —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-, wherein the alkylenegroups are each optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, CN, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃alkyl)amino;

Y is selected from the group consisting of O, C(O), C(O)NR^(f),NR^(f)C(O), and NR^(f);

each R^(f) is independently selected from the group consisting of H andC₁₋₃ alkyl;

R^(N) is selected from the group consisting of H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, and C₁₋₄ haloalkyl;

group A is selected from the group consisting of a 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups;

alternatively, group A is H;

with the proviso that when X is NR^(N), L¹ is —C₁₋₆ alkylene-, L² is—C₁₋₆ alkylene-, and R^(N) is C₁₋₆ alkyl, group A is not H; and

each R^(A) is independently selected from the group consisting of OH,NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino,C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino.

In some embodiments,

Hal is Cl;

X is selected from the group consisting of O and NR^(N);

L¹ is —C₁₋₆ alkylene-, wherein the alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, and amino;

L² is —C₁₋₆ alkylene-, wherein the alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, and amino;

R^(N) is selected from the group consisting of H and C₁₋₆ alkyl;

group A is 5 or 6 membered heteroaryl, which is optionally substitutedby 1, 2, or 3 independently selected R^(A) groups;

alternatively, group A is H;

with the proviso that when X is NR^(N), L¹ is —C₁₋₆ alkylene-, L² is—C₁₋₆ alkylene-, and R^(N) is C₁₋₆ alkyl, group A is not H; and

each R^(A) is independently selected from the group consisting of OH,NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino,C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino

In some embodiments,

Hal is selected from the group consisting of Cl, F, and I;

X is selected from the group consisting of O, S, S(O), S(O)₂, and C(O);

L¹ is selected from the group consisting of —C₁₋₆ alkylene- and —Y—C₁₋₆alkylene-, wherein the alkylene groups are each optionally substitutedwith 1, 2, or 3 substituents independently selected from halo, CN, OH,C₁₋₃ alkoxy, and amino;

Y is selected from the group consisting of O, C(O), —C(O)NH—, —NHC(O)—,NH, and —N(CH₃)—;

L² is —C₁₋₆ alkylene-, wherein the alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃alkyl)amino;

group A is selected from the group consisting of a 5-6 memberedheteroaryl and 4-8 membered heterocycloalkyl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups; and

each R^(A) is independently selected from the group consisting of OH,NO₂, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, and di(C₁₋₆alkyl)amino.

In some embodiments,

Hal is selected from the group consisting of Cl, F, and I;

X is selected from the group consisting of O and S;

L¹ is —C₁₋₆ alkylene-, wherein the alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, and amino;

L² is —C₁₋₆ alkylene-, wherein the alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃alkyl)amino;

group A is 5-6 membered heteroaryl, which is optionally substituted by1, 2, or 3 independently selected R^(A) groups; and

each R^(A) is selected from the group consisting of halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, amino, C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino.

In some embodiments,

Hal is selected from the group consisting of Cl, F, and I;

X is NR^(N);

L¹ is —C₁₋₆ alkylene-, wherein the alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, and amino;

L² is —C₁₋₆ alkylene-, wherein the alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃alkyl)amino;

R^(N) is selected from the group consisting of H and C₁₋₆ alkyl;

group A is selected from the group consisting of a 5 or 6 memberedheteroaryl and 4-10 membered heterocycloalkyl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups; and

R^(A) is selected from the group consisting of OH, NO₂, CN, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino.

In some embodiments,

Hal is selected from the group consisting of Cl, F, and I;

X is NR^(N);

L¹ is —C₁₋₃ alkylene-, wherein the alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, and amino;

L² is —C₁₋₃ alkylene-, wherein the alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃alkyl)amino;

R^(N) is selected from the group consisting of H and C₁₋₃ alkyl;

group A is 5 or 6 membered heteroaryl, which is optionally substitutedby 1, 2, or 3 independently selected R^(A) groups; and

R^(A) is selected from the group consisting of halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, amino, C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino.

In some embodiments, the compound of Formula I is a compound of FormulaIa:

or a pharmaceutically acceptable salt thereof, wherein:

Hal is selected from the group consisting of Cl, F, Br, and I;

X is selected from the group consisting of O, S, S(O), S(O)₂, C(O), andNR^(N);

L¹ is selected from the group consisting of —C₁₋₆ alkylene-, —Y—C₁₋₆alkylene-, —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-, or —(O—C₁₋₄ alkylene)_(m)-,wherein m is an integer from 1 to 5, and wherein the alkylene groups areeach optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl,C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃ alkyl)amino;

L² is selected from the group consisting of —C₁₋₆ alkylene-, —C₁₋₆alkylene-Y—, —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-, and —(C₁₋₄alkylene-O—)_(m)—, wherein m is an integer from 1 to 5, and wherein thealkylene groups are each optionally substituted with 1, 2, or 3substituents independently selected from halo, CN, OH, C₁₋₃ alkyl, C₁₋₃alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, anddi(C₁₋₃ alkyl)amino;

each Y is independently selected from the group consisting of O, S,S(O), S(O)₂, C(O), C(O)NR^(f), NR^(f)C(O), S(O)₂NR^(f), NR^(f)S(O)₂, andNR^(f);

each R^(f) is independently selected from the group consisting of H andC₁₋₃ alkyl;

R^(N) is selected from the group consisting of H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₄ haloalkyl, C₃₋₁₀ cycloalkyl, and 4-10 membered heterocycloalkyl areeach optionally substituted by 1, 2, 3, or 4 independently selected R⁹groups;

group A is selected from the group consisting of a 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups;

alternatively, group A is H;

with the proviso that when X is NR^(N), L¹ is —C₁₋₆ alkylene-, L² is—C₁₋₆ alkylene-, and R^(N) is C₁₋₆ alkyl, group A is not H;

each R^(A) is independently selected from the group consisting of OH,NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino,C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino; and

each R^(g) is independently selected from the group consisting of OH,NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino,C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino.

In some embodiments of a compound of Formula Ia, Hal is selected fromthe group consisting of Cl, F, and I. In some embodiments of a compoundof Formula Ia, Hal is Cl. In some embodiments of a compound of FormulaIa, Hal is F. In some embodiments of a compound of Formula Ia, Hal is I.In some embodiments of a compound of Formula Ia, both Hal groups are Cl.In some embodiments of a compound of Formula Ia, both Hal groups are F.In some embodiments of a compound of Formula Ia, both Hal groups are I.In some embodiments of a compound of Formula Ia, one of the Hal groupsis Cl and another Hal group is F. In some embodiments of a compound ofFormula Ia, one of the Hal groups is Cl and another Hal group is I. Insome embodiments of a compound of Formula Ia, one of the Hal groups is Fand another Hal group is I.

In some embodiments of a compound of Formula Ia, X is selected from thegroup consisting of O, S, and NR^(N). In some embodiments of a compoundof Formula Ia, X is selected from the group consisting of O and NR^(N).In some embodiments of a compound of Formula Ia, X is selected from thegroup consisting of O and —N(C₁₋₆ alkyl)-. In some embodiments of acompound of Formula Ia, X is selected from the group consisting of O and—N(CH₃)—. In some embodiments of a compound of Formula Ia, X is O. Insome embodiments of a compound of Formula Ia, X is NR^(N). In someembodiments of a compound of Formula Ia, —N(C₁₋₆ alkyl)-. In someembodiments of a compound of Formula Ia, —N(CH₃)—.

In some embodiments of a compound of Formula Ia, L¹ is selected from thegroup consisting of —C₁₋₆ alkylene-, —Y—C₁₋₆ alkylene-, and —C₁₋₄alkylene-Y—C₁₋₄ alkylene-, wherein the alkylene groups are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃ alkylamino, anddi(C₁₋₃ alkyl)amino.

In some embodiments of a compound of Formula Ia, L¹ is selected from thegroup consisting of —C₁₋₆ alkylene-, and —Y—C₁₋₆ alkylene-, wherein thealkylene groups are each optionally substituted with 1, 2, or 3substituents independently selected from halo, CN, OH, C₁₋₃ alkoxy, andamino.

In some embodiments of a compound of Formula Ia, L¹ is —C₁₋₆ alkylene-,wherein the alkylene group is optionally substituted with 1, 2, or 3substituents independently selected from halo, CN, OH, C₁₋₃ alkoxy, andamino. In some embodiments of a compound of Formula Ia, L¹ is methylene.

In some embodiments of a compound of Formula Ia, L² is selected from thegroup consisting of —C₁₋₆ alkylene-, —C₁₋₆ alkylene-Y—, and —C₁₋₄alkylene-Y—C₁₋₄ alkylene-, wherein the alkylene groups are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl,C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃ alkyl)amino.

In some embodiments of a compound of Formula Ia, L² is selected from thegroup consisting of —C₁₋₆ alkylene- and —C₁₋₆ alkylene-Y—, wherein thealkylene groups are each optionally substituted with 1, 2, or 3substituents independently selected from halo, CN, OH, C₁₋₃ alkoxy, andamino.

In some embodiments of a compound of Formula Ia, L² is —C₁₋₆ alkylene-,wherein the alkylene group is optionally substituted with 1, 2, or 3substituents independently selected from halo, CN, OH, C₁₋₃ alkoxy, andamino. In some embodiments of a compound of Formula Ia, L² is selectedfrom the group consisting of methylene, ethylene, and butylene.

In some embodiments of a compound of Formula Ia, Y is selected from thegroup consisting of O, C(O), C(O)NR^(f), NR^(f)C(O), and NR. In someembodiments of a compound of Formula Ia, Y is selected from the groupconsisting of O, C(O), —C(O)NH—, —NHC(O)—, NH, and —N(CH₃)—.

In some embodiments of a compound of Formula Ia, R^(N) is selected fromthe group consisting of H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄haloalkyl. In some embodiments of a compound of Formula Ia, R^(N) isselected from the group consisting of H and C₁₋₆ alkyl. In someembodiments of a compound of Formula Ia, R^(N) is H. In some embodimentsof a compound of Formula Ia, R^(N) is C₁₋₆ alkyl. In some embodiments ofa compound of Formula Ia, R^(N) is C₁₋₄ haloalkyl. In some embodimentsof a compound of Formula Ia, R^(N) is —CH₃.

In some embodiments of a compound of Formula Ia, X is selected from thegroup consisting of O, S, S(O), S(O)₂, and C(O); and group A is H. Insome embodiments of a compound of Formula Ia, X is selected from thegroup consisting of O and S; and group A is H. In some embodiments of acompound of Formula Ia, X is O; and group A is H. In some aspects ofthese embodiments, L¹ is selected from the group consisting of —C₁₋₆alkylene-, and —Y—C₁₋₆ alkylene-, wherein the alkylene groups are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, and amino. In some aspects ofthese embodiments, L¹ is —C₁₋₆ alkylene-, wherein the alkylene group isoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, and amino. In some aspects ofthese embodiments, L¹ is methylene. In some aspects of theseembodiments, L² is —C₁₋₆ alkylene-, wherein the alkylene group isoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃ alkylamino, anddi(C₁₋₃ alkyl)amino. In some aspects of these embodiments, L² isselected from the group consisting of ethylene and butylene, each ofwhich is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halo, CN, OH, C₁₋₃alkoxy, amino, methylamino, and dimethylamino. In some aspects of theseembodiments, L² is selected from the group consisting of ethylene andbutylene, each of which is optionally substituted with 1, 2, or 3halogen substituents independently selected from Cl, F, and I. In someaspects of these embodiments, L² is selected from the group consistingof ethylene and butylene, each of which is optionally substituted withone F. In some aspects of these embodiments, L² is fluoroethylene. Insome aspects of these embodiments, L² is fluorobutylene.

In some embodiments of a compound of Formula Ia, X is NR^(N); and groupA is selected from the group consisting of a 5 or 6 membered heteroaryland 4-10 membered heterocycloalkyl, each of which is optionallysubstituted by 1, 2, 3, or 4 independently selected R^(A) groups. Insome embodiments of a compound of Formula Ia, X is NR^(N); and group Ais a 5 or 6 membered heteroaryl, which is optionally substituted by 1,2, or 3 independently selected R^(A) groups. In some embodiments of acompound of Formula Ia, X is —N(C₁₋₆ alkyl)-; and group A is a 5 or 6membered heteroaryl, which is optionally substituted by 1, 2, or 3independently selected R^(A) groups. In some embodiments of a compoundof Formula Ia, X is —N(C₁₋₆ alkyl)-; and group A is triazolyl, which isoptionally substituted by 1, 2, or 3 independently selected R^(A)groups. In some embodiments of a compound of Formula Ia, X is —N(CH₃)—;and group A is triazolyl, which is optionally substituted by 1, 2, or 3independently selected R^(A) groups. In some embodiments of a compoundof Formula Ia, X is —N(CH₃)—; and group A is a triazolyl of Formula A-1:

In some aspects of these embodiments, L¹ is —C₁₋₆ alkylene-, wherein thealkylene group is optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, CN, OH, C₁₋₃ alkoxy, and amino. Insome aspects of these embodiments, L¹ is methylene. In some aspects ofthese embodiments, L² is —C₁₋₆ alkylene-, wherein the alkylene group isoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃ alkylamino, anddi(C₁₋₃ alkyl)amino. In some aspects of these embodiments, L² ismethylene. In some aspects of these embodiments, R^(A) is selected fromthe group consisting of OH, NO₂, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino,C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino. In some aspects of theseembodiments, R^(A) is selected from the group consisting of halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino. In someaspects of these embodiments, R^(A) is C₁₋₆ haloalkyl. In some aspectsof these embodiments, R^(A) is selected from the group consisting of2-fluoroethyl, 3-fluoropropyl, and 4-fluorobutyl. In some aspects ofthese embodiments, R^(A) is 2-fluoroethyl. In some aspects of theseembodiments, R^(A) is 3-fluoropropyl. In some aspects of theseembodiments, R^(A) is 4-fluorobutyl.

In some embodiments of a compound of Formula Ia, group A is H.

In some embodiments of a compound of Formula Ia, group A is selectedfrom the group consisting of a 5 or 6 membered heteroaryl and 4-10membered heterocycloalkyl, each of which is optionally substituted by 1,2, 3, or 4 independently selected R^(A) groups.

In some embodiments of a compound of Formula Ia, group A is 5 or 6membered heteroaryl which is optionally substituted by 1, 2, 3, or 4independently selected R^(A) groups. In some embodiments of a compoundof Formula Ia, group A is 5 membered heteroaryl which is optionallysubstituted by 1, 2, or 3 independently selected R^(A) groups. In someembodiments of a compound of Formula Ia, group A is 6 memberedheteroaryl which is optionally substituted by 1, 2, or 3 independentlyselected R^(A) groups.

In some embodiments of a compound of Formula Ia, group A is selectedfrom the group consisting of pyridinyl, triazinyl, pyridazinyl,pyrimidinyl, and pyrazinyl, each of which is optionally substituted by1, 2, 3, or 4 independently selected R^(A) groups. In some embodimentsof a compound of Formula Ia, group A is selected from the groupconsisting of triazolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl,isothiazolyl, thiazolyl, furanyl, and thiophenyl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups.

In some embodiments of a compound of Formula Ia, group A is triazolyl,which is optionally substituted by 1, 2, 3, or 4 independently selectedR^(A) groups. In some embodiments of a compound of Formula Ia, group Ais triazolyl, which is optionally substituted by 1 R^(A) group.

In some embodiments of a compound of Formula Ia, group A is a triazolylof Formula A-1:

In some embodiments of a compound of Formula Ia, group A is 4-10membered heterocycloalkyl, which is optionally substituted by 1, 2, 3,or 4 independently selected R^(A) groups

In some embodiments of a compound of Formula Ia, R^(A) is C₁₋₆haloalkyl. In some embodiments of a compound of Formula Ia, R^(A) isselected from the group consisting of 2-fluoroethyl, 3-fluoropropyl, and4-fluorobutyl. In some embodiments of a compound of Formula Ia, R^(A) is2-fluoroethyl. In some embodiments of a compound of Formula Ia, R^(A) is3-fluoropropyl. In some embodiments of a compound of Formula Ia, R^(A)is 4-fluorobutyl.

In some embodiments, the compound of Formula Ia is a compound of FormulaIb:

or a pharmaceutically acceptable salt thereof, wherein:

Hal is selected from the group consisting of Cl, F, and I; and

R⁰ is —C₁₋₆ alkyl, which is optionally substituted with 1, 2, or 3substituents independently selected from halo, CN, OH, C₁₋₃ alkoxy,amino, C₁₋₃ alkylamino, and di(C₁₋₃ alkyl)amino.

In some embodiments of a compound of Formula Ib, Hal is Cl. In someembodiments of a compound of Formula Ib, Hal is F. In some embodimentsof a compound of Formula Ib, Hal is I. In some embodiments of a compoundof Formula Ib, both Hal groups are Cl. In some embodiments of a compoundof Formula Ib, both Hal groups are F. In some embodiments of a compoundof Formula Ib, both Hal groups are I. In some embodiments of a compoundof Formula Ib, one of the Hal groups is Cl and another Hal group is F.In some embodiments of a compound of Formula Ib, one of the Hal groupsis Cl and another Hal group is I. In some embodiments of a compound ofFormula Ib, one of the Hal groups is F and another Hal group is I.

In some embodiments of a compound of Formula Ib, R⁰ is C₁₋₆ haloalkyl.In some embodiments of a compound of Formula Ib, R⁰ is C₁₋₄ haloalkyl.

In some embodiments of a compound of Formula Ib, R⁰ is 2-fluoroethyl or4-fluorobutyl. In some embodiments of a compound of Formula Ib, R⁰ is2-fluoroethyl. In some embodiments of a compound of Formula Ib, R⁰ is4-fluorobutyl.

In some embodiments, the compound of Formula Ia is a compound of FormulaIc:

or a pharmaceutically acceptable salt thereof, wherein:

Hal is selected from the group consisting of Cl, F, and I; and

group A is selected from the group consisting of a 5-6 memberedheteroaryl and 4-10 membered heterocycloalkyl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups.

In some embodiments of a compound of Formula Ic, Hal is Cl. In someembodiments of a compound of Formula Ic, Hal is F. In some embodimentsof a compound of Formula Ic, Hal is I. In some embodiments of a compoundof Formula Ic, both Hal groups are Cl. In some embodiments of a compoundof Formula Ic, both Hal groups are F. In some embodiments of a compoundof Formula Ic, both Hal groups are I. In some embodiments of a compoundof Formula Ic, one of the Hal groups is Cl and another Hal group is F.In some embodiments of a compound of Formula Ic, one of the Hal groupsis Cl and another Hal group is I. In some embodiments of a compound ofFormula Ic, one of the Hal groups is F and another Hal group is I.

In some embodiments of a compound of Formula Ic, group A is 5 or 6membered heteroaryl which is optionally substituted by 1, 2, 3, or 4independently selected R^(A) groups. In some embodiments of a compoundof Formula Ic, group A is 5 membered heteroaryl which is optionallysubstituted by 1, 2, or 3 independently selected R^(A) groups. In someembodiments of a compound of Formula Ic, group A is 6 memberedheteroaryl which is optionally substituted by 1, 2, or 3 independentlyselected R^(A) groups.

In some embodiments of a compound of Formula Ic, group A is selectedfrom the group consisting of pyridinyl, triazinyl, pyridazinyl,pyrimidinyl, and pyrazinyl, each of which is optionally substituted by1, 2, 3, or 4 independently selected R^(A) groups. In some embodimentsof a compound of Formula Ic, group A is selected from the groupconsisting of triazolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl,isothiazolyl, thiazolyl, furanyl, and thiophenyl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups.

In some embodiments of a compound of Formula Ic, group A is triazolyl,which is optionally substituted by 1, 2, or 3 independently selectedR^(A) groups.

In some embodiments of a compound of Formula Ic, group A is triazolyl,which is optionally substituted by 1 R^(A) group.

In some embodiments of a compound of Formula Ic, group A is a triazolylof Formula A-1c:

In some embodiments of a compound of Formula Ic, R^(A) is selected fromthe group consisting of OH, NO₂, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino,C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino.

In some embodiments of a compound of Formula Ic, R^(A) is selected fromthe group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, cyano-C₁₋₃ alkyl,and HO—C₁₋₃ alkyl.

In some embodiments of a compound of Formula Ic, R^(A) is C₁₋₆haloalkyl. In some embodiments of a compound of Formula Ic, R^(A) isselected from the group consisting of 2-fluoroethyl, 3-fluoropropyl, and4-fluorobutyl. In some embodiments of a compound of Formula Ic, R^(A) is2-fluoroethyl. In some embodiments of a compound of Formula Ic, R^(A) is3-fluoropropyl. In some embodiments of a compound of Formula Ic, R^(A)is 4-fluorobutyl.

In some embodiments, the compound of Formula I, Ia, or Ib is selectedfrom the group consisting of:

or a pharmaceutically acceptable salt of any of the aforementioned.

In some embodiments, the compound of Formula I, Ia, or Ic is selectedfrom the group consisting of:

or a pharmaceutically acceptable salt thereof.

In some embodiments, a salt of a compound of Formulae I, Ia, Ib, and Icis formed between an acid and a basic group of the compound, such as anamino functional group, or a base and an acidic group of the compound,such as a carboxyl functional group. According to another embodiment,the compound is a pharmaceutically acceptable acid addition salt.

In some embodiments, acids commonly employed to form pharmaceuticallyacceptable salts of the compounds of Formulae I, Ia, Ib, and Ic includeinorganic acids such as hydrogen bisulfide, hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, aswell as organic acids such as para-toluenesulfonic acid, salicylic acid,tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylicacid, fumaric acid, gluconic acid, glucuronic acid, formic acid,glutamic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonicacid, carbonic acid, succinic acid, citric acid, benzoic acid and aceticacid, as well as related inorganic and organic acids. Suchpharmaceutically acceptable salts thus include sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,terephthalate, sulfonate, xylene sulfonate, phenylacetate,phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate,glycolate, maleate, tartrate, methanesulfonate, propanesulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and othersalts. In one embodiment, pharmaceutically acceptable acid additionsalts include those formed with mineral acids such as hydrochloric acidand hydrobromic acid, and especially those formed with organic acidssuch as maleic acid.

In some embodiments, bases commonly employed to form pharmaceuticallyacceptable salts of the compounds of Formulae I, Ia, Ib, and Ic includehydroxides of alkali metals, including sodium, potassium, and lithium;hydroxides of alkaline earth metals such as calcium and magnesium;hydroxides of other metals, such as aluminum and zinc; ammonia, organicamines such as unsubstituted or hydroxyl-substituted mono-, di-, ortri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, ortris-(2-OH—(C₁-C₆)-alkylamine), such asN,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine;pyrrolidine; and amino acids such as arginine, lysine, and the like.

In some embodiments, the compounds of Formulae I, Ia, Ib, and Ic, orpharmaceutically acceptable salts thereof, are substantially isolated.

Labeled Compounds

Another aspect of the present application relates to labeled compoundsof Formulae II, IIa, IIb, IIc, and III, that would be useful in imagingtechniques, diagnosing and monitoring treatment of various diseases andconditions described herein. Such compounds are labeled in so far aseach compound includes at least one radioisotope. In some embodiments,such compounds include one radioisotope.

In some embodiments, the at least one radioisotope is a positronemitter.

In some embodiments, the positron emitter is selected from the groupconsisting of ¹¹C, ¹³N, ¹⁵O, ¹⁸F, ^(34m)Cl, ³⁸K, ⁴⁵Ti, ⁵¹Mn, ^(52m)Mn,⁵²Fe, ⁵⁵Co, ⁶⁰Cu, ⁶¹Cu, ⁶²Cu, ⁶⁴Cu, ⁶⁶Ga, ⁶⁸Ga, ⁷¹As, ⁷²As, ⁷⁴As, ⁷⁵Br,⁷⁶Br, ⁸²Rb, ⁸⁶Y, ⁸⁹Zr, ⁹⁰Nb, ^(94m)Tc, ^(110m)In, ¹¹⁸Sb, ¹²⁰I, ¹²¹I,¹²²I, and ¹²⁴I.

In some embodiments, the positron emitter is ¹¹C or ¹⁸F.

In some embodiments, the positron emitter is selected from the groupconsisting of ¹²⁰I ¹²¹I, ¹²²I, and ¹²⁴I.

In some embodiments, the positron emitter is ¹²⁴I.

In some embodiments, the at least one radioisotope is a gamma emitter.

In some embodiments, gamma emitter is selected from the group consistingof ^(99m)Tc, ¹²⁵I, ¹³¹I and ¹²³I.

In some embodiments, the gamma emitter is ¹²³I.

Accordingly, the present application provides, inter alia, a compound ofFormula (II):

or a pharmaceutically acceptable salt thereof, wherein:

Hal is selected from the group consisting of Cl, F, Br, and I;

n is 1, 2, or 3;

X is selected from the group consisting of O, S, S(O), S(O)₂, C(O), andNR^(N);

L¹ is selected from the group consisting of —C₁₋₆ alkylene-, —Y—C₁₋₆alkylene-, —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-, and —(O—C₁₋₄ alkylene)_(m)-,wherein m is an integer from 1 to 5, and wherein said alkylene groupsare each optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, CN, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃alkyl)amino;

L² is selected from the group consisting of —C₁₋₆ alkylene-, —C₁₋₆alkylene-Y—, —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-, and —(C₁₋₄alkylene-O—)_(m)—, wherein m is an integer from 1 to 5, and wherein saidalkylene groups are each optionally substituted with 1, 2, or 3substituents independently selected from halo, CN, OH, C₁₋₃ alkyl, C₁₋₃alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, anddi(C₁₋₃ alkyl)amino;

each Y is independently selected from the group consisting of O, S,S(O), S(O)₂, C(O), C(O)NR^(f), NR^(f)C(O), S(O)₂NR^(f), NR^(f)S(O)₂, andNR^(f);

each R^(f) is independently selected from the group consisting of H andC₁₋₃ alkyl;

R^(N) is selected from the group consisting of H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₃₋₁₀ cycloalkyl, and 4-10membered heterocycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₄ haloalkyl, C₃₋₁₀ cycloalkyl, and 4-10 memberedheterocycloalkyl are each optionally substituted by 1, 2, 3, or 4independently selected R⁹ groups; group A is selected from the groupconsisting of a 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl, each of which is optionally substituted by 1, 2, 3, or4 independently selected R^(A) groups;

alternatively, group A is H;

with the proviso that when X is NR^(N), L¹ is —C₁₋₆ alkylene-, L² is—C₁₋₆ alkylene-, and R^(N) is C₁₋₆ alkyl, group A is not H;

each R^(A) is independently selected from the group consisting of OH,NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino,C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino;

each R^(g) is independently selected from the group consisting of OH,NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino,C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino; and

wherein the compound of Formula (II) comprises at least oneradioisotope.

In some embodiments, Hal is selected from the group consisting of Cl, F,and I. In some embodiments, Hal is Cl. In some embodiments, Hal is F. Insome embodiments, Hal is I. In some embodiments, both Hal groups are Cl.In some embodiments, both Hal groups are F. In some embodiments, bothHal groups are I. In some embodiments, one of the Hal groups is Cl andanother Hal group is F. In some embodiments, one of the Hal groups is Cland another Hal group is I. In some embodiments, one of the Hal groupsis F and another Hal group is I. In some embodiments, Hal comprises atleast one radioisotope (e.g., ¹⁸F).

In some embodiments, X is selected from the group consisting of O, S,and NR^(N). In some embodiments, X is selected from the group consistingof O and NR^(N). In some embodiments, X is selected from the groupconsisting of O and —N(C₁₋₆ alkyl)-. In some embodiments, X is selectedfrom the group consisting of O and —N(CH₃)—. In some embodiments, X isO. In some embodiments, X is NR^(N). In some embodiments, —N(C₁₋₆alkyl)-. In some embodiments, —N(CH₃)—.

In some embodiments, L¹ is selected from the group consisting of —C₁₋₆alkylene-, —Y—C₁₋₆ alkylene-, and —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-,wherein said alkylene groups are each optionally substituted with 1, 2,or 3 substituents independently selected from halo, CN, OH, C₁₋₃ alkoxy,amino, C₁₋₃ alkylamino, and di(C₁₋₃ alkyl)amino.

In some embodiments, L¹ is selected from the group consisting of —C₁₋₆alkylene-, and —Y—C₁₋₆ alkylene-, wherein said alkylene groups are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, and amino.

In some embodiments, L¹ is —C₁₋₆ alkylene-, wherein said alkylene groupis optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, and amino. In some embodiments,L¹ is methylene.

In some embodiments, L² is selected from the group consisting of —C₁₋₆alkylene-, —C₁₋₆ alkylene-Y—, and —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-,wherein said alkylene groups are each optionally substituted with 1, 2,or 3 substituents independently selected from halo, CN, OH, C₁₋₃ alkyl,C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,and di(C₁₋₃ alkyl)amino.

In some embodiments, L² is selected from the group consisting of —C₁₋₆alkylene- and —C₁₋₆ alkylene-Y—, wherein said alkylene groups are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, and amino.

In some embodiments, L² is —C₁₋₆ alkylene-, wherein said alkylene groupis optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, and amino. In some embodiments,L² is selected from the group consisting of methylene, ethylene, andbutylene.

In some embodiments, Y is selected from the group consisting of O, C(O),C(O)NR^(f), NR^(f)C(O), and NR^(f). In some embodiments, Y is selectedfrom the group consisting of O, C(O), —C(O)NH—, —NHC(O)—, NH, and—N(CH₃)—.

In some embodiments, R^(N) is selected from the group consisting of H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl. In someembodiments, R^(N) is selected from the group consisting of H and C₁₋₆alkyl. In some embodiments, R^(N) is H. In some embodiments, R^(N) isC₁₋₆ alkyl. In some embodiments, R^(N) is C₁₋₄ haloalkyl. In someembodiments, R^(N) is —CH₃.

In some embodiments, X is selected from the group consisting of O, S,S(O), S(O)₂, and C(O); and group A is H. In some embodiments, X isselected from the group consisting of O and S; and group A is H. In someembodiments, X is O; and group A is H. In some aspects of theseembodiments, L¹ is selected from the group consisting of —C₁₋₆alkylene-, and —Y—C₁₋₆ alkylene-, wherein said alkylene groups are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, and amino. In some aspects ofthese embodiments, L¹ is —C₁₋₆ alkylene-, wherein said alkylene group isoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, and amino. In some aspects ofthese embodiments, L¹ is methylene. In some aspects of theseembodiments, L² is —C₁₋₆ alkylene-, wherein said alkylene group isoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃ alkylamino, anddi(C₁₋₃ alkyl)amino. In some aspects of these embodiments, L² isselected from the group consisting of ethylene and butylene, each ofwhich is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halo, CN, OH, C₁₋₃alkoxy, amino, methylamino, and dimethylamino. In some aspects of theseembodiments, L² is selected from the group consisting of ethylene andbutylene, each of which is optionally substituted with 1, 2, or 3halogen substituents independently selected from Cl, F, and I. In someaspects of these embodiments, L² is selected from the group consistingof ethylene and butylene, each of which is optionally substituted withone F. In some aspects of these embodiments, L² is fluoroethylene. Insome aspects of these embodiments, L² is fluorobutylene.

In some embodiments, X is NR^(N); and group A is selected from the groupconsisting of a 5 or 6 membered heteroaryl and 4-10 memberedheterocycloalkyl, each of which is optionally substituted by 1, 2, 3, or4 independently selected R^(A) groups. In some embodiments, X is NR^(N);and group A is a 5 or 6 membered heteroaryl, which is optionallysubstituted by 1, 2, or 3 independently selected R^(A) groups. In someembodiments, X is —N(C₁₋₆ alkyl)-; and group A is a 5 or 6 memberedheteroaryl, which is optionally substituted by 1, 2, or 3 independentlyselected R^(A) groups. In some embodiments, X is —N(C₁₋₆ alkyl)-; andgroup A is triazolyl, which is optionally substituted by 1, 2, or 3independently selected R^(A) groups. In some embodiments, X is —N(CH₃)—;and group A is triazolyl, which is optionally substituted by 1, 2, or 3independently selected R^(A) groups. In some embodiments, X is —N(CH₃)—;and group A is a triazolyl of Formula A-1:

In some aspects of these embodiments, L¹ is —C₁₋₆ alkylene-, whereinsaid alkylene group is optionally substituted with 1, 2, or 3substituents independently selected from halo, CN, OH, C₁₋₃ alkoxy, andamino. In some aspects of these embodiments, L¹ is methylene. In someaspects of these embodiments, L² is —C₁₋₆ alkylene-, wherein saidalkylene group is optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃alkylamino, and di(C₁₋₃ alkyl)amino. In some aspects of theseembodiments, L² is methylene. In some aspects of these embodiments,R^(A) is selected from the group consisting of OH, NO₂, CN, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino. In someaspects of these embodiments, R^(A) is selected from the groupconsisting of halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, anddi(C₁₋₆ alkyl)amino. In some aspects of these embodiments, R^(A) is C₁₋₆haloalkyl. In some aspects of these embodiments, R^(A) is selected fromthe group consisting of 2-fluoroethyl, 3-fluoropropyl, and4-fluorobutyl. In some aspects of these embodiments, R^(A) is2-fluoroethyl. In some aspects of these embodiments, R^(A) is3-fluoropropyl. In some aspects of these embodiments, R^(A) is4-fluorobutyl.

In some embodiments, group A is H.

In some embodiments, group A is selected from the group consisting of a5 or 6 membered heteroaryl and 4-10 membered heterocycloalkyl, each ofwhich is optionally substituted by 1, 2, 3, or 4 independently selectedR^(A) groups.

In some embodiments, group A is 5 or 6 membered heteroaryl which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups. In some embodiments, group A is 5 membered heteroaryl which isoptionally substituted by 1, 2, or 3 independently selected R^(A)groups. In some embodiments, group A is 6 membered heteroaryl which isoptionally substituted by 1, 2, or 3 independently selected R^(A)groups.

In some embodiments, group A is selected from the group consisting ofpyridinyl, triazinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, each ofwhich is optionally substituted by 1, 2, 3, or 4 independently selectedR^(A) groups. In some embodiments, group A is selected from the groupconsisting of triazolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl,isothiazolyl, thiazolyl, furanyl, and thiophenyl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups.

In some embodiments, group A is triazolyl, which is optionallysubstituted by 1, 2, 3, or 4 independently selected R^(A) groups. Insome embodiments, group A is triazolyl, which is optionally substitutedby 1 R^(A) group.

In some embodiments, group A is a triazolyl of Formula A-1:

In some embodiments, group A is 4-10 membered heterocycloalkyl, which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups

In some embodiments, R^(A) is C₁₋₆ haloalkyl. In some embodiments, R^(A)is selected from the group consisting of 2-fluoroethyl, 3-fluoropropyl,and 4-fluorobutyl. In some embodiments, R^(A) is 2-fluoroethyl. In someembodiments, R^(A) is 3-fluoropropyl. In some embodiments, R^(A) is4-fluorobutyl.

In some embodiments,

Hal is selected from the group consisting of Cl, F, and I;

X is selected from the group consisting of O, S, and NR^(N);

L¹ is selected from the group consisting of —C₁₋₆ alkylene-, —Y—C₁₋₆alkylene-, and —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-, wherein said alkylenegroups are each optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃alkylamino, and di(C₁₋₃ alkyl)amino;

L² is selected from the group consisting of —C₁₋₆ alkylene-, —C₁₋₆alkylene-Y—, and —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-, wherein said alkylenegroups are each optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, CN, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃alkyl)amino;

Y is selected from the group consisting of O, C(O), C(O)NR^(f),NR^(f)C(O), and NR^(f);

each R^(f) is independently selected from the group consisting of H andC₁₋₃ alkyl;

R^(N) is selected from the group consisting of H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, and C₁₋₄ haloalkyl;

group A is selected from the group consisting of a 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups;

alternatively, group A is H;

with the proviso that when X is NR^(N), L¹ is —C₁₋₆ alkylene-, L² is—C₁₋₆ alkylene-, and R^(N) is C₁₋₆ alkyl, group A is not H; and

each R^(A) is independently selected from the group consisting of OH,NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino,C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino.

In some embodiments,

Hal is Cl;

X is selected from the group consisting of O and NR^(N);

L¹ is —C₁₋₆ alkylene-, wherein said alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, and amino;

L² is —C₁₋₆ alkylene-, wherein said alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, and amino;

R^(N) is selected from the group consisting of H and C₁₋₆ alkyl;

group A is 5 or 6 membered heteroaryl, which is optionally substitutedby 1, 2, or 3 independently selected R^(A) groups;

alternatively, group A is H;

with the proviso that when X is NR^(N), L¹ is —C₁₋₆ alkylene-, L² is—C₁₋₆ alkylene-, and R^(N) is C₁₋₆ alkyl, group A is not H; and

each R^(A) is independently selected from the group consisting of OH,NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino,C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino

In some embodiments,

Hal is selected from the group consisting of Cl, F, and I;

X is selected from the group consisting of O, S, S(O), S(O)₂, and C(O);

L¹ is selected from the group consisting of —C₁₋₆ alkylene- and —Y—C₁₋₆alkylene-, wherein said alkylene groups are each optionally substitutedwith 1, 2, or 3 substituents independently selected from halo, CN, OH,C₁₋₃ alkoxy, and amino;

Y is selected from the group consisting of O, C(O), —C(O)NH—, —NHC(O)—,NH, and —N(CH₃)—;

L² is —C₁₋₆ alkylene-, wherein said alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃alkyl)amino;

group A is selected from the group consisting of a 5-6 memberedheteroaryl and 4-8 membered heterocycloalkyl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups; and

each R^(A) is independently selected from the group consisting of OH,NO₂, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, and di(C₁₋₆alkyl)amino.

In some embodiments,

Hal is selected from the group consisting of Cl, F, and I;

X is selected from the group consisting of O and S;

L¹ is —C₁₋₆ alkylene-, wherein said alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, and amino;

L² is —C₁₋₆ alkylene-, wherein said alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃alkyl)amino;

group A is 5-6 membered heteroaryl, which is optionally substituted by1, 2, or 3 independently selected R^(A) groups; and

each R^(A) is selected from the group consisting of halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, amino, C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino.

In some embodiments,

Hal is selected from the group consisting of Cl, F, and I;

X is NR^(N);

L¹ is —C₁₋₆ alkylene-, wherein said alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, and amino;

L² is —C₁₋₆ alkylene-, wherein said alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃alkyl)amino;

R^(N) is selected from the group consisting of H and C₁₋₆ alkyl;

group A is selected from the group consisting of a 5 or 6 memberedheteroaryl and 4-10 membered heterocycloalkyl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups; and

R^(A) is selected from the group consisting of OH, NO₂, CN, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino.

In some embodiments,

Hal is selected from the group consisting of Cl, F, and I;

X is NR^(N);

L¹ is —C₁₋₃ alkylene-, wherein said alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, and amino;

L² is —C₁₋₃ alkylene-, wherein said alkylene group is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃alkyl)amino;

R^(N) is selected from the group consisting of H and C₁₋₃ alkyl;

group A is 5 or 6 membered heteroaryl, which is optionally substitutedby 1, 2, or 3 independently selected R^(A) groups; and

R^(A) is selected from the group consisting of halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, amino, C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino.

In some embodiments, the compound of Formula II is a compound of FormulaIIa:

or a pharmaceutically acceptable salt thereof, wherein:

Hal is selected from the group consisting of Cl, F, Br, and I;

X is selected from the group consisting of O, S, S(O), S(O)₂, C(O), andNR^(N);

L¹ is selected from the group consisting of —C₁₋₆ alkylene-, —Y—C₁₋₆alkylene-, —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-, and —(O—C₁₋₄ alkylene)_(m)-,wherein m is an integer from 1 to 5, and wherein said alkylene groupsare each optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, CN, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃alkyl)amino;

L² is selected from the group consisting of —C₁₋₆ alkylene-, —C₁₋₆alkylene-Y—, —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-, or —(C₁₋₄alkylene-O—)_(m)—, wherein m is an integer from 1 to 5, and wherein saidalkylene groups are each optionally substituted with 1, 2, or 3substituents independently selected from halo, CN, OH, C₁₋₃ alkyl, C₁₋₃alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, anddi(C₁₋₃ alkyl)amino;

each Y is independently selected from the group consisting of O, S,S(O), S(O)₂, C(O), C(O)NR^(f), NR^(f)C(O), S(O)₂NR^(f), NR^(f)S(O)₂, andNR^(f);

each R^(f) is independently selected from the group consisting of H andC₁₋₃ alkyl;

R^(N) is selected from the group consisting of H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₃₋₁₀ cycloalkyl, and 4-10membered heterocycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₄ haloalkyl, C₃₋₁₀ cycloalkyl, and 4-10 memberedheterocycloalkyl are each optionally substituted by 1, 2, 3, or 4independently selected R⁹ groups;

group A is selected from the group consisting of a 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups;

alternatively, group A is H;

with the proviso that when X is NR^(N), L¹ is —C₁₋₆ alkylene-, L² is—C₁₋₆ alkylene-, and R^(N) is C₁₋₆ alkyl, group A is not H;

each R^(A) is independently selected from the group consisting of OH,NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino,C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino;

each R^(g) is independently selected from the group consisting of OH,NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino,C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino; and

wherein the compound of Formula (IIa) comprises at least oneradioisotope.

In some embodiments of a compound of Formula IIa, Hal is selected fromthe group consisting of Cl, F, and I. In some embodiments of a compoundof Formula IIa, Hal is Cl. In some embodiments of a compound of FormulaIIa, Hal is F. In some embodiments of a compound of Formula IIa, Hal isI. In some embodiments of a compound of Formula IIa, both Hal groups areCl. In some embodiments of a compound of Formula IIa, both Hal groupsare F. In some embodiments of a compound of Formula IIa, both Hal groupsare I. In some embodiments of a compound of Formula IIa, one of the Halgroups is Cl and another Hal group is F. In some embodiments of acompound of Formula IIa, one of the Hal groups is Cl and another Halgroup is I. In some embodiments of a compound of Formula IIa, one of theHal groups is F and another Hal group is I. In some embodiments, Halcomprises at least one radioisotope (e.g., ¹⁸F).

In some embodiments of a compound of Formula IIa, X is selected from thegroup consisting of O, S, and NR^(N). In some embodiments of a compoundof Formula IIa, X is selected from the group consisting of O and NR^(N).In some embodiments of a compound of Formula IIa, X is selected from thegroup consisting of O and —N(C₁₋₆ alkyl)-. In some embodiments of acompound of Formula IIa, X is selected from the group consisting of Oand —N(CH₃)—. In some embodiments of a compound of Formula IIa, X is O.In some embodiments of a compound of Formula IIa, X is NR^(N). In someembodiments of a compound of Formula IIa, —N(C₁₋₆ alkyl)-. In someembodiments of a compound of Formula IIa, —N(CH₃)—.

In some embodiments of a compound of Formula IIa, L¹ is selected fromthe group consisting of —C₁₋₆ alkylene-, —Y—C₁₋₆ alkylene-, and —C₁₋₄alkylene-Y—C₁₋₄ alkylene-, wherein said alkylene groups are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃ alkylamino, anddi(C₁₋₃ alkyl)amino.

In some embodiments of a compound of Formula IIa, L¹ is selected fromthe group consisting of —C₁₋₆ alkylene-, and —Y—C₁₋₆ alkylene-, whereinsaid alkylene groups are each optionally substituted with 1, 2, or 3substituents independently selected from halo, CN, OH, C₁₋₃ alkoxy, andamino.

In some embodiments of a compound of Formula IIa, L¹ is —C₁₋₆ alkylene-,wherein said alkylene group is optionally substituted with 1, 2, or 3substituents independently selected from halo, CN, OH, C₁₋₃ alkoxy, andamino. In some embodiments of a compound of Formula IIa, L¹ ismethylene.

In some embodiments of a compound of Formula IIa, L² is selected fromthe group consisting of —C₁₋₆ alkylene-, —C₁₋₆ alkylene-Y—, and —C₁₋₄alkylene-Y—C₁₋₄ alkylene-, wherein said alkylene groups are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl,C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃ alkyl)amino.

In some embodiments of a compound of Formula IIa, L² is selected fromthe group consisting of —C₁₋₆ alkylene- and —C₁₋₆ alkylene-Y—, whereinsaid alkylene groups are each optionally substituted with 1, 2, or 3substituents independently selected from halo, CN, OH, C₁₋₃ alkoxy, andamino.

In some embodiments of a compound of Formula IIa, L² is —C₁₋₆ alkylene-,wherein said alkylene group is optionally substituted with 1, 2, or 3substituents independently selected from halo, CN, OH, C₁₋₃ alkoxy, andamino. In some embodiments of a compound of Formula IIa, L² is selectedfrom the group consisting of methylene, ethylene, and butylene.

In some embodiments of a compound of Formula IIa, Y is selected from thegroup consisting of O, C(O), C(O)NR^(f), NR^(f)C(O), and NR^(f). In someembodiments of a compound of Formula IIa, Y is selected from the groupconsisting of O, C(O), —C(O)NH—, —NHC(O)—, NH, and —N(CH₃)—.

In some embodiments of a compound of Formula IIa, R^(N) is selected fromthe group consisting of H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄haloalkyl. In some embodiments of a compound of Formula IIa, R^(N) isselected from the group consisting of H and C₁₋₆ alkyl. In someembodiments of a compound of Formula IIa, R^(N) is H. In someembodiments of a compound of Formula IIa, R^(N) is C₁₋₆ alkyl. In someembodiments of a compound of Formula IIa, R^(N) is C₁₋₄ haloalkyl. Insome embodiments of a compound of Formula IIa, R^(N) is —CH₃.

In some embodiments of a compound of Formula IIa, X is selected from thegroup consisting of O, S, S(O), S(O)₂, and C(O); and group A is H. Insome embodiments of a compound of Formula IIa, X is selected from thegroup consisting of O and S; and group A is H. In some embodiments of acompound of Formula IIa, X is O; and group A is H. In some aspects ofthese embodiments, L¹ is selected from the group consisting of —C₁₋₆alkylene-, and —Y—C₁₋₆ alkylene-, wherein said alkylene groups are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, and amino. In some aspects ofthese embodiments, L¹ is —C₁₋₆ alkylene-, wherein said alkylene group isoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, and amino. In some aspects ofthese embodiments, L¹ is methylene. In some aspects of theseembodiments, L² is —C₁₋₆ alkylene-, wherein said alkylene group isoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃ alkylamino, anddi(C₁₋₃ alkyl)amino. In some aspects of these embodiments, L² isselected from the group consisting of ethylene and butylene, each ofwhich is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halo, CN, OH, C₁₋₃alkoxy, amino, methylamino, and dimethylamino. In some aspects of theseembodiments, L² is selected from the group consisting of ethylene andbutylene, each of which is optionally substituted with 1, 2, or 3halogen substituents independently selected from Cl, F, and I. In someaspects of these embodiments, L² is selected from the group consistingof ethylene and butylene, each of which is optionally substituted withone F. In some aspects of these embodiments, L² is fluoroethylene. Insome aspects of these embodiments, L² is fluorobutylene.

In some embodiments of a compound of Formula IIa, X is NR^(N); and groupA is selected from the group consisting of a 5 or 6 membered heteroaryland 4-10 membered heterocycloalkyl, each of which is optionallysubstituted by 1, 2, 3, or 4 independently selected R^(A) groups. Insome embodiments of a compound of Formula IIa, X is NR^(N); and group Ais a 5 or 6 membered heteroaryl, which is optionally substituted by 1,2, or 3 independently selected R^(A) groups. In some embodiments of acompound of Formula IIa, X is —N(C₁₋₆ alkyl)-; and group A is a 5 or 6membered heteroaryl, which is optionally substituted by 1, 2, or 3independently selected R^(A) groups. In some embodiments of a compoundof Formula IIa, X is —N(C₁₋₆ alkyl)-; and group A is triazolyl, which isoptionally substituted by 1, 2, or 3 independently selected R^(A)groups. In some embodiments of a compound of Formula IIa, X is —N(CH₃)—;and group A is triazolyl, which is optionally substituted by 1, 2, or 3independently selected R^(A) groups. In some embodiments of a compoundof Formula IIa, X is —N(CH₃)—; and group A is a triazolyl of FormulaA-1:

In some aspects of these embodiments, L¹ is —C₁₋₆ alkylene-, whereinsaid alkylene group is optionally substituted with 1, 2, or 3substituents independently selected from halo, CN, OH, C₁₋₃ alkoxy, andamino. In some aspects of these embodiments, L¹ is methylene. In someaspects of these embodiments, L² is —C₁₋₆ alkylene-, wherein saidalkylene group is optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃alkylamino, and di(C₁₋₃ alkyl)amino. In some aspects of theseembodiments, L² is methylene. In some aspects of these embodiments,R^(A) is selected from the group consisting of OH, NO₂, CN, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino. In someaspects of these embodiments, R^(A) is selected from the groupconsisting of halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, anddi(C₁₋₆ alkyl)amino. In some aspects of these embodiments, R^(A) is C₁₋₆haloalkyl. In some aspects of these embodiments, R^(A) is selected fromthe group consisting of 2-fluoroethyl, 3-fluoropropyl, and4-fluorobutyl. In some aspects of these embodiments, R^(A) is2-fluoroethyl. In some aspects of these embodiments, R^(A) is3-fluoropropyl. In some aspects of these embodiments, R^(A) is4-fluorobutyl.

In some embodiments of a compound of Formula IIa, group A is H.

In some embodiments of a compound of Formula IIa, group A is selectedfrom the group consisting of a 5 or 6 membered heteroaryl and 4-10membered heterocycloalkyl, each of which is optionally substituted by 1,2, 3, or 4 independently selected R^(A) groups.

In some embodiments of a compound of Formula IIa, group A is 5 or 6membered heteroaryl which is optionally substituted by 1, 2, 3, or 4independently selected R^(A) groups. In some embodiments of a compoundof Formula IIa, group A is 5 membered heteroaryl which is optionallysubstituted by 1, 2, or 3 independently selected R^(A) groups. In someembodiments of a compound of Formula IIa, group A is 6 memberedheteroaryl which is optionally substituted by 1, 2, or 3 independentlyselected R^(A) groups.

In some embodiments of a compound of Formula IIa, group A is selectedfrom the group consisting of pyridinyl, triazinyl, pyridazinyl,pyrimidinyl, and pyrazinyl, each of which is optionally substituted by1, 2, 3, or 4 independently selected R^(A) groups. In some embodimentsof a compound of Formula IIa, group A is selected from the groupconsisting of triazolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl,isothiazolyl, thiazolyl, furanyl, and thiophenyl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups.

In some embodiments of a compound of Formula IIa, group A is triazolyl,which is optionally substituted by 1, 2, 3, or 4 independently selectedR^(A) groups. In some embodiments of a compound of Formula IIa, group Ais triazolyl, which is optionally substituted by 1 R^(A) group.

In some embodiments of a compound of Formula IIa, group A is a triazolylof Formula A-1:

In some embodiments of a compound of Formula IIa, group A is 4-10membered heterocycloalkyl, which is optionally substituted by 1, 2, 3,or 4 independently selected R^(A) groups

In some embodiments of a compound of Formula IIa, R^(A) is C₁₋₆haloalkyl. In some embodiments of a compound of Formula IIa, R^(A) isselected from the group consisting of 2-fluoroethyl, 3-fluoropropyl, and4-fluorobutyl. In some embodiments of a compound of Formula IIa, R^(A)is 2-fluoroethyl. In some embodiments of a compound of Formula IIa,R^(A) is 3-fluoropropyl. In some embodiments of a compound of FormulaIIa, R^(A) is 4-fluorobutyl.

In some embodiments, the compound of Formula IIa is a compound ofFormula IIb:

or a pharmaceutically acceptable salt thereof, wherein:

Hal is selected from the group consisting of Cl, F, and I; and

R⁰ is —C₁₋₆ alkyl, which is optionally substituted with 1, 2, or 3substituents independently selected from halo, CN, OH, C₁₋₃ alkoxy,amino, C₁₋₃ alkylamino, and di(C₁₋₃ alkyl)amino;

wherein the compound of Formula (IIb) comprises at least oneradioisotope.

In some embodiments of a compound of Formula IIb, Hal is Cl. In someembodiments of a compound of Formula IIb, Hal is F. In some embodimentsof a compound of Formula IIb, Hal is I. In some embodiments of acompound of Formula IIb, both Hal groups are Cl. In some embodiments ofa compound of Formula IIb, both Hal groups are F. In some embodiments ofa compound of Formula IIb, both Hal groups are I. In some embodiments ofa compound of Formula IIb, one of the Hal groups is Cl and another Halgroup is F. In some embodiments of a compound of Formula IIb, one of theHal groups is Cl and another Hal group is I. In some embodiments of acompound of Formula IIb, one of the Hal groups is F and another Halgroup is I. In some embodiments, Hal comprises at least one radioisotope(e.g., ¹⁸F).

In some embodiments of a compound of Formula IIb, R⁰ is C₁₋₆ haloalkyl.In some embodiments of a compound of Formula IIb, R⁰ is C₁₋₄ haloalkyl.

In some embodiments of a compound of Formula IIb, R⁰ is 2-fluoroethyl or4-fluorobutyl. In some embodiments of a compound of Formula IIb, R⁰ is2-fluoroethyl. In some embodiments of a compound of Formula IIb, R⁰ is4-fluorobutyl.

In some embodiments of a compound of Formula IIb, one of Hal is aradioisotope.

In some embodiments of a compound of Formula IIb, Hal is selected fromthe group consisting of ¹⁸F, ⁷⁵Br, ⁷⁶Br, ¹²⁰I, ¹²¹I, ¹²²I, ¹²⁵I, ¹³¹I,¹²³I, and ¹²⁴I.

In some embodiments of a compound of Formula IIb, Hal is ¹⁸F or ¹²³I

In some embodiments of a compound of Formula IIb, R⁰ comprises oneradioisotope.

In some embodiments of a compound of Formula IIb, R⁰ is selected fromthe group consisting of ¹⁸F, ⁷⁵Br, ⁷⁶Br, ¹²⁰I, ¹²¹I, ¹²²I, ¹²⁵I, ¹³¹I,¹²³I, and ¹²⁴I.

In some embodiments of a compound of Formula IIb, R⁰ is ¹⁸F. In someembodiments of a compound of Formula IIb, R⁰ is ¹²³I

In some embodiments, the compound of Formula IIa is a compound ofFormula IIc:

or a pharmaceutically acceptable salt thereof, wherein:

Hal is selected from the group consisting of Cl, F, and I;

group A is selected from the group consisting of a 5-6 memberedheteroaryl and 4-10 membered heterocycloalkyl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups; and

wherein the compound of Formula (IIc) comprises at least oneradioisotope.

In some embodiments of a compound of Formula IIc, Hal is Cl. In someembodiments of a compound of Formula IIc, Hal is F. In some embodimentsof a compound of Formula IIc, Hal is I. In some embodiments of acompound of Formula IIc, both Hal groups are Cl. In some embodiments ofa compound of Formula IIc, both Hal groups are F. In some embodiments ofa compound of Formula IIc, both Hal groups are I. In some embodiments ofa compound of Formula IIc, one of the Hal groups is Cl and another Halgroup is F. In some embodiments of a compound of Formula IIc, one of theHal groups is Cl and another Hal group is I. In some embodiments of acompound of Formula IIc, one of the Hal groups is F and another Halgroup is I.

In some embodiments of a compound of Formula IIc, group A is 5 or 6membered heteroaryl which is optionally substituted by 1, 2, 3, or 4independently selected R^(A) groups. In some embodiments of a compoundof Formula IIc, group A is 5 membered heteroaryl which is optionallysubstituted by 1, 2, or 3 independently selected R^(A) groups. In someembodiments of a compound of Formula IIc, group A is 6 memberedheteroaryl which is optionally substituted by 1, 2, or 3 independentlyselected R^(A) groups.

In some embodiments of a compound of Formula IIc, group A is selectedfrom the group consisting of pyridinyl, triazinyl, pyridazinyl,pyrimidinyl, and pyrazinyl, each of which is optionally substituted by1, 2, 3, or 4 independently selected R^(A) groups. In some embodimentsof a compound of Formula IIc, group A is selected from the groupconsisting of triazolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl,isothiazolyl, thiazolyl, furanyl, and thiophenyl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups.

In some embodiments of a compound of Formula IIc, group A is triazolyl,which is optionally substituted by 1, 2, or 3 independently selectedR^(A) groups.

In some embodiments of a compound of Formula IIc, group A is triazolyl,which is optionally substituted by 1 R^(A) group.

In some embodiments of a compound of Formula IIc, group A is a triazolylof Formula A-1c:

In some embodiments of a compound of Formula IIc, R^(A) is selected fromthe group consisting of OH, NO₂, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino,C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino.

In some embodiments of a compound of Formula IIc, R^(A) is selected fromthe group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, cyano-C₁₋₃ alkyl,and HO—C₁₋₃ alkyl.

In some embodiments of a compound of Formula IIc, R^(A) is C₁₋₆haloalkyl. In some embodiments of a compound of Formula IIc, R^(A) isselected from the group consisting of 2-fluoroethyl, 3-fluoropropyl, and4-fluorobutyl. In some embodiments of a compound of Formula IIc, R^(A)is 2-fluoroethyl. In some embodiments of a compound of Formula IIc,R^(A) is 3-fluoropropyl. In some embodiments of a compound of FormulaIIc, R^(A) is 4-fluorobutyl.

In some embodiments of a compound of Formula IIc, R^(A) comprises atleast one radioisotope.

In some embodiments of a compound of Formula IIc, R^(A) comprises oneradioisotope.

In some embodiments of a compound of Formula IIc, R^(A) comprises one ormore of ¹⁸F, ⁷⁵Br, ⁷⁶Br, ¹²⁰I, ¹²¹I, ¹²²I, ¹²⁵I, ¹³¹I, ¹²³I, and 124I.

In some embodiments of a compound of Formula IIc, R^(A) comprises ¹⁸F.In some embodiments of a compound of Formula IIc, R^(A) comprises ¹²³I

In some embodiments, R^(N) comprises at least one radioisotope.

In some embodiments, R^(N) comprises one radioisotope.

In some embodiments, R^(N) comprises ¹¹C.

In some embodiments, L² comprises at least one radioisotope.

In some embodiments, L² comprises one radioisotope.

In some embodiments, L² comprises ¹⁸F or ¹¹C.

In some embodiments, L² comprises ¹⁸F.

In some embodiments, at least one of Hal groups is a radioisotope.

In some embodiments, one of Hal groups is a radioisotope.

In some embodiments, one of Hal groups is selected from the groupconsisting of ¹⁸F, ⁷⁵Br, ⁷⁶Br, ¹²⁰I, ¹²¹I, ¹²²I, ¹²⁵I, ¹³¹I, ¹²³I, and¹²⁴I.

In some embodiments, one of Hal groups is ¹⁸F or ¹²³I.

In some embodiments, one of Hal groups is ¹⁸F.

In some embodiments, one of Hal groups is ¹²³I.

In some embodiments, the compound of any of Formulae II, IIa, IIb, andIIc comprises one radioisotope.

In some embodiments, the compound of Formula II, IIa, or Ib is selectedfrom the group consisting of:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula II, IIa, or IIc is selectedfrom the group consisting of:

or a pharmaceutically acceptable salt thereof.

Also provided herein is a compound of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein:

each X¹ and X² is independently selected from the group consisting of F,Cl, Br, and I;

wherein at least one of X¹ and X² comprises a radioisotope; and wherein:

when X¹ is I or F, then X² is not Cl; and

when X¹ is I, then X² is not F.

In some embodiments, X¹ is F and X² is Br.

In some embodiments, X¹ is F and X² is I.

In some embodiments, X¹ is Cl and X² is F.

In some embodiments, X¹ is Br and X² is F.

In some embodiments, X¹ is F and X² is F.

In some embodiments, X¹ is I and X² is Br.

In some embodiments, X¹ is ¹⁸F and X² is Br

In some embodiments, X¹ is ¹⁸F and X² is I.

In some embodiments, X¹ is F and X² is ¹²³I.

In some embodiments, X¹ is F and X² is ¹²⁴I.

In some embodiments, X¹ is Cl and X² is ¹⁸F.

In some embodiments, X¹ is Br and X² is ¹⁸F.

In some embodiments, X¹ is ¹⁸F and X² is F.

In some embodiments, X¹ is F and X² is ¹⁸F.

In some embodiments, X¹ is ¹⁸F and X² is ¹⁸F.

In some embodiments, X¹ is ¹²³I and X² is Br.

In some embodiments, X¹ is ¹²⁴I and X² is Br.

In some embodiments, when X¹ is ¹²³I or ¹⁸F, then X² is not Cl. In someembodiments, when X¹ is ¹²³I, then X² is not Cl. In some embodiments,when X¹ is ¹⁸F, then X² is not Cl.

In some embodiments, when X¹ is I, then X² is not ¹⁸F.

In one embodiment, the compound of Formula III is selected from thegroup consisting of:

or a pharmaceutically acceptable salt thereof.

In some embodiments, compounds of Formulae II, IIa, IIb, IIc, and IIIcan include all isotopes of atoms occurring in the intermediates orfinal compounds. Isotopes include those atoms having the same atomicnumber but different mass numbers

In some embodiments, when an atom in compounds of Formulae II, IIa, IIb,IIc, and III is designated as an isotope or radioisotope (e.g., [¹¹C],[¹⁸F], [¹²³I]), the atom is understood to comprise the isotope orradioisotope in an amount at least greater than the natural abundance ofthe isotope or radioisotope. For example, when an atom is designated as“D” or “deuterium”, the position is understood to have deuterium at anabundance that is at least 3000 times greater than the natural abundanceof deuterium, which is 0.015% (i.e., at least 45% incorporation ofdeuterium).

In some embodiments, compounds of Formulae II, IIa, IIb, IIc, and IIIhave an isotopic enrichment factor for each designated radioisotope atomof at least 3500 (52.5% radioisotope incorporation at each designatedradioisotope atom), at least 4000 (60% radioisotope incorporation), atleast 4500 (67.5% radioisotope incorporation), at least 5000 (75%radioisotope), at least 5500 (82.5% radioisotope incorporation), atleast 6000 (90% radioisotope incorporation), at least 6333.3 (95%radioisotope incorporation), at least 6466.7 (97% radioisotopeincorporation), at least 6600 (99% radioisotope incorporation), or atleast 6633.3 (99.5% radioisotope incorporation).

In some embodiments, a salt of a compound of Formulae II, IIa, IIb, IIc,and III is formed between an acid and a basic group of the compound,such as an amino functional group, or a base and an acidic group of thecompound, such as a carboxyl functional group. According to anotherembodiment, the compound is a pharmaceutically acceptable acid additionsalt.

In some embodiments, acids commonly employed to form pharmaceuticallyacceptable salts of the compounds Formulae II, IIa, IIb, IIc, and IIIinclude inorganic acids such as hydrogen bisulfide, hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, aswell as organic acids such as para-toluenesulfonic acid, salicylic acid,tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylicacid, fumaric acid, gluconic acid, glucuronic acid, formic acid,glutamic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonicacid, carbonic acid, succinic acid, citric acid, benzoic acid and aceticacid, as well as related inorganic and organic acids. Suchpharmaceutically acceptable salts thus include sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,terephthalate, sulfonate, xylene sulfonate, phenylacetate,phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate,glycolate, maleate, tartrate, methanesulfonate, propanesulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and othersalts. In one embodiment, pharmaceutically acceptable acid additionsalts include those formed with mineral acids such as hydrochloric acidand hydrobromic acid, and especially those formed with organic acidssuch as maleic acid.

In some embodiments, bases commonly employed to form pharmaceuticallyacceptable salts of the compounds of Formulae II, IIa, IIb, IIc, and IIIinclude hydroxides of alkali metals, including sodium, potassium, andlithium; hydroxides of alkaline earth metals such as calcium andmagnesium; hydroxides of other metals, such as aluminum and zinc;ammonia, organic amines such as unsubstituted or hydroxyl-substitutedmono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine;pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-,bis-, or tris-(2-OH—(C₁-C₆)-alkylamine), such asN,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine;pyrrolidine; and amino acids such as arginine, lysine, and the like.

In some embodiments, the compounds of Formulae II, IIa, IIb, IIc, andIII, or pharmaceutically acceptable salts thereof, are substantiallyisolated.

Pharmaceutical Compositions and Formulations

The present application also provides pharmaceutical compositionscomprising an effective amount of a compound of any one of Formulae I,Ia, Ib, Ic, II, IIa, IIb, IIc, and III, or a pharmaceutically acceptablesalt thereof; and a pharmaceutically acceptable carrier. The carrier(s)are “acceptable” in the sense of being compatible with the otheringredients of the formulation and, in the case of a pharmaceuticallyacceptable carrier, not deleterious to the recipient thereof in anamount used in the medicament.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may beused in the pharmaceutical compositions of the present applicationinclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, potassium sorbate,partial glyceride mixtures of saturated vegetable fatty acids, water,salts or electrolytes, such as protamine sulfate, disodium hydrogenphosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol, andwool fat.

If required, the solubility and bioavailability of the compounds of thepresent application in pharmaceutical compositions may be enhanced bymethods well-known in the art. One method includes the use of lipidexcipients in the formulation. See “Oral Lipid-Based Formulations:Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs andthe Pharmaceutical Sciences),” David J. Hauss, ed. Informa Healthcare,2007; and “Role of Lipid Excipients in Modifying Oral and ParenteralDrug Delivery: Basic Principles and Biological Examples,” Kishor M.Wasan, ed. Wiley-Interscience, 2006.

Another known method of enhancing bioavailability is the use of anamorphous form of a compound of the present application optionallyformulated with a poloxamer, such as LUTROL™ and PLURONIC™ (BASFCorporation), or block copolymers of ethylene oxide and propylene oxide.See U.S. Pat. No. 7,014,866; and United States patent publications20060094744 and 20060079502.

The pharmaceutical compositions of the present application include thosesuitable for oral, rectal, nasal, topical (including buccal andsublingual), vaginal or parenteral (including subcutaneous,intramuscular, intravenous and intradermal) administration. In certainembodiments, the compound of the formulae herein is administeredtransdermally (e.g., using a transdermal patch or iontophoretictechniques). Other formulations may conveniently be presented in unitdosage form, e.g., tablets, sustained release capsules, and inliposomes, and may be prepared by any methods well known in the art ofpharmacy. See, for example, Remington: The Science and Practice ofPharmacy, Lippincott Williams & Wilkins, Baltimore, Md. (20th ed. 2000).

Such preparative methods include the step of bringing into associationwith the molecule to be administered ingredients such as the carrierthat constitutes one or more accessory ingredients. In general, thecompositions are prepared by uniformly and intimately bringing intoassociation the active ingredients with liquid carriers, liposomes orfinely divided solid carriers, or both, and then, if necessary, shapingthe product.

In some embodiments, the compound any one of Formulae I, Ia, Ib, Ic, II,IIa, IIb, IIc, and III is administered orally. Compositions of thepresent application suitable for oral administration may be presented asdiscrete units such as capsules, sachets, or tablets each containing apredetermined amount of the active ingredient; a powder or granules; asolution or a suspension in an aqueous liquid or a non-aqueous liquid;an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packedin liposomes; or as a bolus, etc. Soft gelatin capsules can be usefulfor containing such suspensions, which may beneficially increase therate of compound absorption.

In the case of tablets for oral use, carriers that are commonly usedinclude lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. For oral administration in a capsuleform, useful diluents include lactose and dried cornstarch. When aqueoussuspensions are administered orally, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweeteningand/or flavoring and/or coloring agents may be added.

Compositions suitable for oral administration include lozengescomprising the ingredients in a flavored basis, usually sucrose andacacia or tragacanth; and pastilles comprising the active ingredient inan inert basis such as gelatin and glycerin, or sucrose and acacia.

Compositions suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain antioxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example, sealed ampules and vials, and may be stored ina freeze dried (lyophilized) condition requiring only the addition ofthe sterile liquid carrier, for example water for injections,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tablets.

Such injection solutions may be in the form, for example, of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to techniques known in the art using suitabledispersing or wetting agents (such as, for example, Tween 80) andsuspending agents. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are mannitol, water, Ringer's solution and isotonic sodiumchloride solution. In addition, sterile, fixed oils are conventionallyemployed as a solvent or suspending medium. For this purpose, any blandfixed oil may be employed including synthetic mono- or diglycerides.Fatty acids, such as oleic acid and its glyceride derivatives are usefulin the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions may also contain a long-chain alcohol diluent or dispersant.

The pharmaceutical compositions of the present application may beadministered in the form of suppositories for rectal administration.These compositions can be prepared by mixing a compound of the presentapplication with a suitable non-irritating excipient which is solid atroom temperature but liquid at the rectal temperature and therefore willmelt in the rectum to release the active components. Such materialsinclude, but are not limited to, cocoa butter, beeswax, and polyethyleneglycols.

The pharmaceutical compositions of the present application may beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other solubilizing or dispersingagents known in the art. See, for example, U.S. Pat. No. 6,803,031.

Topical administration of the pharmaceutical compositions of the presentapplication is especially useful when the desired treatment involvesareas or organs readily accessible by topical application. For topicalapplication topically to the skin, the pharmaceutical composition shouldbe formulated with a suitable ointment containing the active componentssuspended or dissolved in a carrier. Carriers for topical administrationof the compounds of the present application include, but are not limitedto, mineral oil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax, and water.Alternatively, the pharmaceutical composition can be formulated with asuitable lotion or cream containing the active compound suspended ordissolved in a carrier. Suitable carriers include, but are not limitedto, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esterswax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. Thepharmaceutical compositions of the present application may also betopically applied to the lower intestinal tract by rectal suppositoryformulation or in a suitable enema formulation. Topically-transdermalpatches and iontophoretic administration are also included in thepresent application.

Application of the subject therapeutics may be local, so as to beadministered at the site of interest. Various techniques can be used forproviding the subject compositions at the site of interest, such asinjection, use of catheters, trocars, projectiles, pluronic gel, stents,sustained drug release polymers or other device which provides forinternal access.

Thus, according to yet another embodiment, the compounds of the presentapplication may be incorporated into compositions for coating animplantable medical device, such as prostheses, artificial valves,vascular grafts, stents, or catheters. Suitable coatings and the generalpreparation of coated implantable devices are known in the art and areexemplified in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. Thecoatings are typically biocompatible polymeric materials such as ahydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethyleneglycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.The coatings may optionally be further covered by a suitable topcoat offluorosilicone, polysaccharides, polyethylene glycol, phospholipids orcombinations thereof to impart controlled release characteristics in thecomposition. Coatings for invasive devices are to be included within thedefinition of pharmaceutically acceptable carrier, adjuvant or vehicle,as those terms are used herein.

According to another embodiment, the present application provides amethod of coating an implantable medical device comprising the step ofcontacting said device with the coating composition described above. Itwill be obvious to those skilled in the art that the coating of thedevice will occur prior to implantation into a mammal.

According to another embodiment, the present application provides amethod of impregnating an implantable drug release device comprising thestep of contacting said drug release device with a compound orcomposition of the present application. Implantable drug release devicesinclude, but are not limited to, biodegradable polymer capsules orbullets, non-degradable, diffusible polymer capsules and biodegradablepolymer wafers.

According to another embodiment, the present application provides animplantable medical device coated with a compound or a compositioncomprising a compound of the present application, such that saidcompound is therapeutically active.

According to another embodiment, the present application provides animplantable drug release device impregnated with or containing acompound or a composition comprising a compound of the presentapplication, such that said compound is released from said device and istherapeutically active.

Where an organ or tissue is accessible because of removal from thesubject, such organ or tissue may be bathed in a medium containing acomposition of the present application, a composition of the presentapplication may be painted onto the organ, or a composition of thepresent application may be applied in any other convenient way.

In another embodiment, a composition of the present application furthercomprises a second therapeutic agent. The second therapeutic agent maybe selected from any compound or therapeutic agent known to have or thatdemonstrates advantageous properties when administered with a compoundhaving the same mechanism of action as a compound of any one of FormulaeI, Ia, Ib, Ic, II, IIa, IIb, IIc, and III. Such agents include thoseindicated as being useful in combination with a compound of any one ofFormulae I, Ia, Ib, Ic, II, IIa, IIb, IIc, and III, including but notlimited to, an inhibitor of the acetylcholinesterase active site, forexample phenserine, galantamine, or tacrine; an antioxidant, such asVitamin E or Vitamin C; an anti-inflammatory agent such as flurbiprofenor ibuprofen optionally modified to release nitric oxide (for exampleNCX-2216, produced by NicOx) or an oestrogenic agent such as17-β-oestradiol.

In some embodiments, a compound of any one of Formulae I, Ia, Ib, Ic,II, IIa, IIb, IIc, and III can be used in combination with achemotherapeutic agent, surgical cancer treatment, or radiotherapy. Insome embodiments, chemotherapeutic agents include, for example,antimetabolites (including, without limitation, folic acid antagonists,pyrimidine analogs, purine analogs and adenosine deaminase inhibitors)such as methotrexate, 5-fluorouracil, floxuridine, cytarabine,6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine,and gemcitabine. In some embodiments, chemotherapeutic agents include,for example, alkylating agents (including, without limitation, nitrogenmustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas andtriazenes) such as uracil mustard, chlormethine, cyclophosphamide(Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman,triethylene-melamine, triethylenethio, phosphoramine, busulfan,carmustine, lomustine, streptozocin, dacarbazine, and temozolomide

In another embodiment, the present application provides separate dosageforms of a compound of any one of Formulae I, Ia, Ib, Ic, II, IIa, IIb,IIc, and III and one or more of any of the above-described secondtherapeutic agents, wherein the compound and second therapeutic agentare associated with one another. The term “associated with one another”as used herein means that the separate dosage forms are packagedtogether or otherwise attached to one another such that it is readilyapparent that the separate dosage forms are intended to be sold andadministered together (within less than 24 hours of one another,consecutively or simultaneously).

In the pharmaceutical compositions of the present application, acompound of any one of Formulae I, Ia, Ib, Ic, II, IIa, IIb, IIc, andIII is present in an effective amount (e.g., a therapeutically effectiveamount).

The interrelationship of dosages for animals and humans (based onmilligrams per meter squared of body surface) is described in Freireichet al., Cancer Chemother. Rep, 1966, 50: 219. Body surface area may beapproximately determined from height and weight of the subject. See,e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 1970,537.

In some embodiments, an effective amount of a compound of any one ofFormulae I, Ia, Ib, Ic, II, IIa, IIb, IIc, and III can range, forexample, from about 10 mg to about 2000 mg, from about 10 mg to about1900 mg, from about 10 mg to about 1800 mg, from about 10 mg to about1700 mg, from about 10 mg to about 1600 mg, from about 10 mg to about1500 mg, from about 10 mg mg to about 1400 mg, from about 10 mg to about1300 mg, from about 10 mg to about 1200 mg, from about 10 mg to about1100 mg, from about 10 mg to about 1000 mg, from 10 mg about to about900 mg, from about 10 mg to about 800 mg, from about 10 mg to about 700mg, from about 10 mg to about 600 mg, from about 10 mg to about 500 mg,from about 10 mg to about 400 mg, from about 10 mg to about 300 mg, fromabout 10 mg to about 200 mg, from about 10 mg to about 100 mg, and fromabout 10 mg to about 50 mg. In some aspects of these embodiments, thecomposition containing an effective amount of a compound of any one ofFormulae I, Ia, Ib, Ic, II, IIa, IIb, IIc, and III is administered oncedaily. In some aspects of these embodiments, the composition containingan effective amount of a compound of any one of Formulae I, Ia, Ib, Ic,II, IIa, IIb, IIc, and III is administered twice daily. In some aspectsof these embodiments, the composition containing an effective amount ofa compound of any one of Formulae I, Ia, Ib, Ic, II, IIa, IIb, IIc, andIII is administered thrice daily.

In some embodiments, an effective amount of a compound of any one ofFormulae I, Ia, Ib, Ic, II, IIa, IIb, IIc, and III can range, forexample, from about 1 mg/kg to about 500 mg/kg, from about 1 mg/kg toabout 200 mg/kg, from about 1 mg/kg to about 100 mg/kg, from about 1mg/kg to about 50 mg/kg, from about 1 mg/kg to about 40 mg/kg, fromabout 1 mg/kg to about 30 mg/kg, from about 1 mg/kg to about 20 mg/kg,from about 1 mg/kg to about 10 mg/kg, from about 2 mg/kg to about 400mg/kg, from about 3 mg/kg to about 300 mg/kg, from about 4 mg/kg toabout 200 mg/kg, from about 5 mg/kg to about 100 mg/kg, from about 10mg/kg to about 500 mg/kg, from about 10 mg/kg to about 400 mg/kg, fromabout 10 mg/kg to about 300 mg/kg, from about 10 mg/kg to about 200mg/kg, from about 10 mg/kg to about 100 mg/kg, and from about 10 mg/kgto about 50 mg/kg. In some aspects of these embodiments, the compositioncontaining an effective amount of a compound of any one of Formulae I,Ia, Ib, Ic, II, IIa, IIb, IIc, and III is administered once daily. Insome aspects of these embodiments, the composition containing aneffective amount of a compound of any one of Formulae I, Ia, Ib, Ic, II,IIa, IIb, IIc, and III is administered twice daily. In some aspects ofthese embodiments, the composition containing an effective amount of acompound of any one of Formulae I, Ia, Ib, Ic, II, IIa, IIb, IIc, andIII is administered thrice daily.

In some embodiments, an effective amount of a compound of any one ofFormulae I, Ia, Ib, Ic, II, IIa, IIb, IIc, and III can be, for example,1 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, or100 mg/kg. In some aspects of these embodiments, the compositioncontaining an effective amount of a compound of any one of Formulae I,Ia, Ib, Ic, II, IIa, IIb, IIc, and III is administered once daily. Insome aspects of these embodiments, the composition containing aneffective amount of a compound of any one of Formulae I, Ia, Ib, Ic, II,IIa, IIb, IIc, and III is administered twice daily. In some aspects ofthese embodiments, the composition containing an effective amount of acompound of any one of Formulae I, Ia, Ib, Ic, II, IIa, IIb, IIc, andIII is administered thrice daily.

Effective doses will also vary, as recognized by those skilled in theart, depending on the diseases treated, the severity of the disease, theroute of administration, the sex, age and general health condition ofthe subject, excipient usage, the possibility of co-usage with othertherapeutic treatments such as use of other agents and the judgment ofthe treating physician. For example, guidance for selecting an effectivedose can be determined by reference to the prescribing information forCompound 1.

For pharmaceutical compositions that comprise a second therapeuticagent, an effective amount of the second therapeutic agent is betweenabout 20% and 100% of the dosage normally utilized in a monotherapyregime using just that agent. Preferably, an effective amount is betweenabout 70% and 100% of the normal monotherapeutic dose. The normalmonotherapeutic dosages of these second therapeutic agents are wellknown in the art. See, e.g., Wells et al., eds., PharmacotherapyHandbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDRPharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition,Tarascon Publishing, Loma Linda, Calif. (2000), each of which referencesare incorporated herein by reference in their entirety.

It is expected that some of the second therapeutic agents referencedabove will act synergistically with the compounds of the presentapplication. When this occurs, it will allow the effective dosage of thesecond therapeutic agent and/or the compound of the present applicationto be reduced from that required in a monotherapy. This has theadvantage of minimizing toxic side effects of either the secondtherapeutic agent of a compound of the present application, synergisticimprovements in efficacy, improved ease of administration or use and/orreduced overall expense of compound preparation or formulation.

Synthesis

Compounds provided herein, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes.

It will be appreciated by one skilled in the art that the processesdescribed are not the exclusive means by which compounds provided hereinmay be synthesized and that a broad repertoire of synthetic organicreactions is available to be potentially employed in synthesizingcompounds provided herein. The person skilled in the art knows how toselect and implement appropriate synthetic routes. Suitable syntheticmethods of starting materials, intermediates and products may beidentified by reference to the literature, including reference sourcessuch as: Advances in Heterocyclic Chemistry, Vols. 1-107 (Elsevier,1963-2012); Journal of Heterocyclic Chemistry Vols. 1-49 (Journal ofHeterocyclic Chemistry, 1964-2012); Carreira, et al. (Ed.) Science ofSynthesis, Vols. 1-48 (2001-2010) and Knowledge Updates KU2010/1-4;2011/1-4; 2012/1-2 (Thieme, 2001-2012); Katritzky, et al. (Ed.)Comprehensive Organic Functional Group Transformations, (Pergamon Press,1996); Katritzky et al. (Ed.); Comprehensive Organic Functional GroupTransformations II (Elsevier, 2^(nd) Edition, 2004); Katritzky et al.(Ed.), Comprehensive Heterocyclic Chemistry (Pergamon Press, 1984);Katritzky et al., Comprehensive Heterocyclic Chemistry II, (PergamonPress, 1996); Smith et al., March's Advanced Organic Chemistry:Reactions, Mechanisms, and Structure, 6^(th) Ed. (Wiley, 2007); Trost etal. (Ed.), Comprehensive Organic Synthesis (Pergamon Press, 1991).

The reactions for preparing the compounds provided herein can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of the compounds provided herein can involve the protectionand deprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in P. G. M. Wuts and T. W.Greene, Protective Groups in Organic Synthesis, 4^(th) Ed., Wiley &Sons, Inc., New York (2006).

The compounds of Formula I provided herein can be prepared according toScheme 1. For example, 8-hydorxyquinoline derivative 1-1 can be firstprotected with a Boc group, followed by an oxidation reaction, such asSeO₂ oxidation, and subsequent deprotection, to yield aldehyde 1-2. WhenX is O, the subsequent reduction with a reducing reagent, such as NABH₄,can lead to oxygen-containing intermediate 1-3. When X is NR^(N),reacting aldehyde 1-2 with a substituted amine HNR^(N) leads to theintermediate Shiff-base, which as further reduced in-situ by using areducing agent, such as NaBH₄, to yield a nitrogen-containingintermediate 2-3. The following reaction, such as alkylation reaction,with an intermediate 1-4 using an appropriate leaving group (LG) leadsto the compounds of Formula I.

The compounds of Formula Ia can be prepared according to Scheme 2. Forexample, 8-hydorxyquinoline derivative 2-1 can be first protected with aBoc group, followed by an oxidation reaction, such as SeO₂ oxidation,and subsequent deprotection, to yield aldehyde 2-2. When X is O, thesubsequent reduction with a reducing reagent, such as NABH₄, can lead tooxygen-containing intermediate 2-3. When X is NR^(N), reacting aldehyde2-2 with a substituted amine HNR^(N) leads to the intermediateShiff-base, which is further reduced in-situ by using a reducing agent,such as NaBH₄, to yield a nitrogen-containing intermediate 2-3. Thefollowing reaction, such as an alkylation reaction, with an intermediate1-4 using an appropriate leaving group (LG) leads to the compounds ofFormula Ia.

The compounds of Formula Ib can be prepared according to Scheme 3. Forexample, 8-hydorxyquinoline derivative 3-1 can be first protected with aBoc group, followed by an oxidation reaction, such as SeO₂ oxidation,and subsequent deprotection, to yield aldehyde 3-2. Aldehyde 3-2 can befurther reduced by using, for example, NaBH₄. Subsequent alkylationreaction of 3-3 with LG-R⁰ alkylating reagent 3-4, wherein LG is anappropriate leaving group such as tosylate, leads to compounds ofFormula Ib.

The fluorinated ethers 3a-1 can be prepared from alcohols 3-3 usingalkylating reagents such as fluoroalkyl tosylate, in the presence of abase such as NaH, according to Scheme 3a. The hydroxyl group of 3-3 canbe protected prior to the alkylation step and deprotected after thealkylation step. The suitable protecting group is, for example, aBOC-protecting group.

The compounds of Formula Ic can be prepared according to Scheme 4. Forexample, aldehyde 3-2 can react with an amide such as methylamine toyield the intermediate Shiff-base 4-1. Subsequent reduction of theShiff-base 4-1 with a reducing agent such as NaBH₄ produces secondaryamine 4-2. Alkylating the secondary amine 4-2 with an alkylating agent4-3, wherein LG is a suitable leaving group such as halide (e.g.,bromide) and RG1 is a reactive group such as alkyne, leads to a reactiveintermediate 4-4. Reacting 4-4 with group 4-5, wherein RG2 is a reactivegroup such as azide, yields the compounds of Formula Ic.

Triazole compounds 4a-2 can be prepared according to Scheme 4a. Forexample, secondary amine 4-2 can react with haloalkyne such as3-bromopropyne, in the presence of a tertiary amine such as DIPEA, toarrive at the alkyne derivatives 4a-1. The alkynes 4a-1 can subsequentlyreact with fluoroalkyl azide, such as fluoroethyl azide, in the presenceof a suitable catalyst, such as CuSO₄×5H₂O and sodium ascorbate, toarrive at compounds 4a-2.

Compounds of Formulae II, IIa, IIb, and IIc can be prepared fromstarting materials containing at least one radioisotope according to themethods and procedures described for the compounds of Formulae I, Ia,Ib, and Ic. Synthetic methods for incorporating radioisotopes intoorganic compounds are well known in the art, and one of ordinary skillin the art will readily recognize the methods applicable for thecompounds of Formulae II, IIa, IIb, and IIc.

In one embodiment, radiolabeling of compounds of any one the FormulaeII, IIa, IIb, and IIc can be carried out using the procedures analogousto those outlined in Scheme 5.

wherein LG is a suitable leaving group, and the radiolabeling reagentcontains ¹⁸F.

In one embodiment, radiolabeling of compounds of any one the FormulaeII, IIa, IIb, and IIc can be carried out using the procedures analogousto those outlined in Scheme 6.

wherein the radiolabeling can be conducted using ¹¹C-enriched methylhalide, such as methyl iodide.

In one embodiment, radiolabeling of compounds of any one the FormulaeII, IIa, IIb, and IIc can be carried out using the procedures analogousto those outlined in Scheme 7.

wherein LG is a suitable leaving group, and the radiolabeling reagentcontains ¹⁸F.

Compounds of Formula III can be prepared from starting materialscontaining at least one radioisotope. Synthetic methods forincorporating radioisotopes into organic compounds are well known in theart, and one of ordinary skill in the art will readily recognize themethods applicable for the synthesis of compounds of Formula III.

In one embodiment, radiolabeling of compounds of Formula III can becarried out using the procedures analogous to those outlined in Scheme8.

wherein LG is a suitable leaving group, and the radiolabeling reagentcontains ¹⁸F or ¹²³I.

Methods of Use

Methods of Treatment:

Provided in the present application are methods of treating a disease ordisorder in a subject in need thereof. In some embodiments, the methodcomprises administering to the subject a therapeutically effectiveamount of a compound provided herein (e.g., a compound of Formula I, Ia,Ib, or Ic), or a pharmaceutically acceptable salt thereof.

In some embodiments, the present application provides a method oftreating a neurological disorder in a subject in need thereof, themethod comprising administering to the subject a therapeuticallyeffective amount of a compound of any one of Formulae I, Ia, Ib, and Ic,or a pharmaceutically acceptable salt thereof.

In some embodiments, the neurological disorder is a neurodegenerativedisease.

In some embodiments, the neurodegenerative disease is selected from thegroup consisting of Alzheimer's disease (AD), Parkinson's disease (PD),Huntington's Disease (HD), motor neurone disease (MND), and Priondisease.

In some embodiments, the neurodegenerative disease is Alzheimer'sdisease (AD).

In some embodiments, the neurological disorder is selected from thegroup consisting of cerebral amyloid angiopathy, vascular cognitiveimpairment (VCI), dementia, dementia with Lewy bodies, frontotemporaldementia (FTD), amyotrophic lateral sclerosis (ALS), multiple sclerosis,hippocampal sclerosis, Binswanger's disease, and Creutzfeldt-Jakobdisease.

In some embodiments, the neurological disorder is selected from thegroup consisting of AIDS dementia and HIV-1 induced neurotoxicity;Alzheimer's disease; amylotrophic lateral sclerosis, cerebral ischaemia,cerebrovascular ischemia, brain ischemia, cerebral palsy; cerebraltumour; chemotherapy-induced brain damage; cisplatin-inducedneurotoxicity, Creutzfeldt-Jacob disease and its new variant associatedwith “mad cow” disease; diabetic neuropathy; Down's syndrome; drowning;epilepsy and post-traumatic epilepsy; Friedreich's ataxia;frontotemporal dementia; Hallervorden-Spatz disease; Huntington'sdisease; Lewy body disease; stroke, ischaemic stroke; masculardegeneration; methanol-induced neurotoxicity; meningitis (aseptic andtuberculous); motor neuron disease; multiple sclerosis; multiple systematrophy; neoplasia; Parkinson's disease; perinatal asphyxia; Pick'sdisease; progressive supra-nuclear palsy; radiotherapy-induced braindamage; senile dementia; schizophrenia; depression, major depressivedisorder, subharrachnoid haemorrage/cerebral vasospasm; surgical trauma,including neurosurgery; neurosurgical trauma, transient ischaemic attack(TIA); traumatic brain injury (TBI); traumatic spinal injury; vasculardementia; viral meningitis; encephalitis, and viral encephalitis.

In some embodiments, the present application provides a method oftreating cancer in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of acompound of any one of Formulae I, Ia, Ib, and Ic, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the cancer is selected from the group consisting ofbladder cancer, brain cancer, breast cancer, colorectal cancer, cervicalcancer, gastrointestinal cancer, genitourinary cancer, head and neckcancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer,renal cancer, skin cancer, and testicular cancer.

In some embodiments, the cancer is prostate cancer.

In some embodiments, cancer is selected from the group selected fromsarcoma, angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma,myxoma, rhabdomyoma, fibroma, lipoma, teratoma, lung cancer,bronchogenic carcinoma squamous cell, undifferentiated small cell,undifferentiated large cell, adenocarcinoma, alveolar bronchiolarcarcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatoushamartoma, mesothelioma, gastrointestinal cancer, cancer of theesophagus, squamous cell carcinoma, adenocarcinoma, leiomyosarcoma,lymphoma, cancer of the stomach, carcinoma, lymphoma, leiomyosarcoma,cancer of the pancreas, ductal adenocarcinoma, insulinoma, glucagonoma,gastrinoma, carcinoid tumor, vipoma, cancer of the small bowel,adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma,hemangioma, lipoma, neurofibroma, fibroma, cancer of the large bowel orcolon, tubular adenoma, villous adenoma, hamartoma, leiomyoma,genitourinary tract cancer, cancer of the kidney adenocarcinoma, Wilm'stumor (nephroblastoma), lymphoma, leukemia, cancer of the bladder,cancer of the urethra, squamous cell carcinoma, transitional cellcarcinoma, cancer of the prostate, cancer of the testis, seminoma,teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma,sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoidtumors, lipoma, liver cancer, hepatoma hepatocellular carcinoma,cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, hemangioma, bone cancer, osteogenic sarcoma (osteosarcoma),fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing'ssarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma,malignant giant cell tumor, chordoma, osteochrondroma(osteocartilaginous exostoses), benign chondroma, chondroblastoma,chondromyxofibroma, osteoid osteoma giant cell tumor, nervous systemcancer, cancer of the skull, osteoma, hemangioma, granuloma, xanthoma,osteitis deformans, cancer of the meninges meningioma, meningiosarcoma,gliomatosis, cancer of the brain, astrocytoma, medulloblastoma, glioma,ependymoma, germinoma (pinealoma), glioblastoma multiforme,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, cancerof the spinal cord, neurofibroma, meningioma, glioma, sarcoma,gynecological cancer, cancer of the uterus, endometrial carcinoma,cancer of the cervix, cervical carcinoma, pre tumor cervical dysplasia,cancer of the ovaries, ovarian carcinoma, serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma, granulosa-thecacell tumor, Sertoli Leydig cell tumor, dysgerminoma, malignant teratoma,cancer of the vulva, squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma, cancer of the vagina, clear cellcarcinoma, squamous cell carcinoma, botryoid sarcoma, embryonalrhabdomyosarcoma, cancer of the fallopian tubes, hematologic cancer,cancer of the blood, acute myeloid leukemia (AML), chronic myeloidleukemia (CML), acute lymphoblastic leukemia (ALL), chroniclymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferativediseases, multiple myeloma, myelodysplastic syndrome, Hodgkin'slymphoma, non-Hodgkin's lymphoma (malignant lymphoma), Waldenstrom'smacroglobulinemia, skin cancer, malignant melanoma, basal cellcarcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplasticnevi, lipoma, angioma, dermatofibroma, keloids, psoriasis, adrenal glandcancer, and neuroblastoma.

Methods of Diagnosis, Imaging, and Monitoring Treatment:

Provided in the present application are methods of imaging the brain ofa subject in need of such imaging. In some embodiments, the methodcomprises administering to the subject an effective amount of a compoundof any one of Formulae II, IIA, Ib, Ic, and III, or a pharmaceuticallyacceptable salt thereof. In further embodiments, the method compriseswaiting a time sufficient to allow the compound to accumulate in thebrain to be imaged. In yet further embodiments, the method comprisesimaging the brain with an imaging technique.

Provided in the present application are methods of diagnosing aneurological disorder in a subject in need of such diagnosis. In someembodiments, the method comprises administering to the subject aneffective amount of a compound of any one of Formulae II, IIa, IIb, IIc,and III, or a pharmaceutically acceptable salt thereof. In furtherembodiments, the method comprises waiting a time sufficient to allow thecompound to accumulate at a tissue or cell site associated with theneurological disorder. In yet further embodiments, the method comprisesimaging the cell or tissue with an imaging technique.

Provided in the present application are methods of monitoring treatmentof a neurological disorder in a subject in need of such monitoring. Insome embodiments, the method comprises imaging a cell or tissue with animaging technique. In further embodiments, the method comprisesadministering to the subject an effective amount of a compound of anyone of Formulae II, IIa, IIb, IIc, and III, or a pharmaceuticallyacceptable salt thereof. In further embodiments, the method compriseswaiting a time sufficient to allow the compound to accumulate at atissue or cell site associated with the neurological disorder. Infurther embodiments, the method comprises imaging the cell or tissuewith an imaging technique after administration of a compound of any oneof Formulae II, IIa, IIb, IIc, and III to the subject and waiting thetime sufficient to allow the compound to accumulate at a tissue or cellsite associated with the neurological disorder. In yet furtherembodiments, the method comprises comparing the image obtained beforeadministration of a compound of any one of Formulae II, IIa, IIb, IIc,and III with the image obtained after administration of the compound.

In some embodiments, the present application provides a method ofimaging the brain of a subject, the method comprising:

-   -   i) administering to the subject an effective amount of a        compound of any one of Formulae II, IIa, IIb, IIc, and III, or a        pharmaceutically acceptable salt thereof,    -   ii) waiting a time sufficient to allow the compound to        accumulate in the brain to be imaged; and    -   iii) imaging the brain with an imaging technique.

In some embodiments, the present application provides a method ofdiagnosing a neurological disorder in a subject, the method comprising:

-   -   i) administering to the subject a compound of any one of        Formulae II, IIa, IIb, IIc, and III;    -   ii) waiting a time sufficient to allow the compound to        accumulate at a tissue or cell site associated with the        neurological disorder;    -   iii) imaging the cell or tissue with an imaging technique;

In some embodiments, the method further comprises determining thediagnosis of the neurological disorder in the subject. In someembodiments, the method further comprises providing the diagnosis of theneurological disorder to the subject.

In some embodiments, the present application provides a method ofmonitoring treatment of a neurological disorder in a subject, the methodcomprising:

-   -   i) imaging a cell or tissue with an imaging technique;    -   ii) administering to the subject a compound of any one of        Formulae II, IIa, IIb, IIc, and III in an effective amount of to        treat the neurological disorder;    -   iii) waiting a time sufficient to allow the compound to        accumulate at a tissue or cell site associated with the        neurological disorder;    -   iv) imaging the cell or tissue with an imaging technique; and    -   v) comparing the image of step i) and the image of step iv).

In some embodiments, the method further comprises determiningprogression or regression of a neurological disorder in a subject. Insome embodiments, the method further comprises providing results ofdetermination to the subject.

In some embodiments, the neurological disorder is a neurodegenerativedisease.

In some embodiments, neurodegenerative disease is selected from any oneof the neurodegenerative diseases described herein.

In some embodiments, neurodegenerative disease is Alzheimer's disease(AD).

In some embodiments, neurological disorder is selected from any one ofthe neurological disorders described herein.

Provided in the present application are methods of diagnosing cancer ina subject in need of such diagnosis. In some embodiments, the methodcomprises administering to the subject an effective amount of a compoundof any one of Formulae II, IIa, IIb, IIc, and III, or a pharmaceuticallyacceptable salt thereof. In further embodiments, the method compriseswaiting a time sufficient to allow the compound to accumulate at atissue or cell site associated with cancer. In yet further embodiments,the method comprises imaging the cell or tissue with an imagingtechnique.

Provided in the present application are methods of monitoring treatmentof cancer in a subject in need of such monitoring. In some embodiments,the method comprises imaging a cell or tissue with an imaging technique.In further embodiments, the method comprises administering to thesubject an effective amount of a compound of any one of Formulae II,IIa, IIb, IIc, and III, or a pharmaceutically acceptable salt thereof.In further embodiments, the method comprises waiting a time sufficientto allow the compound to accumulate at a tissue or cell site associatedwith the cancer. In further embodiments, the method comprises imagingthe cell or tissue with an imaging technique after administration of thecompound of any one of Formulae II, IIa, IIb, IIc, and III to thesubject and waiting the time sufficient to allow the compound toaccumulate at a tissue or cell site associated with cancer. In yetfurther embodiments, the method comprises comparing the image obtainedbefore administration of a compound of any one of Formulae II, IIa, IIb,IIc, and III with the image obtained after administration of thecompound.

In some embodiments, the present application provides a method ofdiagnosing cancer in a subject, the method comprising:

-   -   i) administering to the subject a compound of any one of        Formulae II, IIa, IIb, IIc, and III;    -   ii) waiting a time sufficient to allow the compound to        accumulate at a tissue or cell site associated with the cancer;        and    -   iii) imaging the cell or tissue with an imaging technique.

In some embodiments, the method further comprises determining thediagnosis of the cancer in the subject. In some embodiments, the methodfurther comprises providing the diagnosis of cancer to the subject.

In some embodiments, the present application provides a method ofmonitoring treatment of a cancer in a subject, the method comprising:

-   -   i) imaging a cell or tissue with an imaging technique;    -   ii) administering to the subject a compound of any one of        Formulae II, IIa, IIb, IIc, and III in an effective amount of to        treat the cancer;    -   iii) waiting a time sufficient to allow the compound to        accumulate at a tissue or cell site associated with the cancer;    -   iv) imaging the cell or tissue with an imaging technique; and    -   v) comparing the image of step i) and the image of step iv).

In some embodiments, the method further comprises determiningprogression or regression of cancer in a subject. In some embodiments,the method further comprises providing results of determination to thesubject.

In some embodiments, the cancer is selected from any one of the cancersdescribed herein.

In some embodiments, the imaging technique is selected from the groupconsisting of magnetic resonance imaging, optical imaging, single-photonemission computer tomography, positron emission tomography imaging,positron emission tomography with computer tomography imaging, andpositron emission tomography with magnetic resonance imaging.

In some embodiments, the imaging technique is selected from the groupconsisting of positron emission tomography (PET) and single-photonemission computer tomography (SPECT).

In some embodiments, the imaging technique is positron emissiontomography (PET).

In some embodiments, the imaging technique is single-photon emissioncomputer tomography (SPECT).

In some embodiments, any determination of results of imaging, diagnosis,or monitoring of treatment is performed by a skilled physician,according to the relevant circumstances, including the condition to betreated, the chosen route of administration, the actual compoundadministered, the age, weight, and response of the individual subject,the severity of the subject's symptoms, and the like.

Definitions

At various places in the present specification, substituents ofcompounds of the present application are disclosed in groups or inranges. It is specifically intended that various embodiments of thepresent application include each and every individual subcombination ofthe members of such groups and ranges. For example, the term “C₁₋₆alkyl” is specifically intended to individually disclose methyl, ethyl,C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted. As used herein, the term “substituted” means that ahydrogen atom is removed and replaced by a substituent. It is to beunderstood that substitution at a given atom is limited by valency.

Throughout the definitions, the term “C_(n-m)” indicates a range whichincludes the endpoints, wherein n and m are integers and indicate thenumber of carbons. Examples include C₁₋₄, C₁₋₆, and the like.

As used herein, the term “C_(n-m) alkyl”, employed alone or incombination with other terms, refers to a saturated hydrocarbon groupthat may be straight-chain or branched, having n to m carbons. Examplesof alkyl moieties include, but are not limited to, chemical groups suchas methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl,sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl,n-hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, thealkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms,from 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

As used herein, “C_(n-m) alkenyl” refers to an alkyl group having one ormore double carbon-carbon bonds and having n to m carbons. Examplealkenyl groups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl, and the like. In some embodiments,the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, “C_(n-m) alkynyl” refers to an alkyl group having one ormore triple carbon-carbon bonds and having n to m carbons. Examplealkynyl groups include, but are not limited to, ethynyl, propyn-1-yl,propyn-2-yl, and the like. In some embodiments, the alkynyl moietycontains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylene”, employed alone or incombination with other terms, refers to a divalent alkyl linking grouphaving n to m carbons. Examples of alkylene groups include, but are notlimited to, ethan-1,1-diyl, ethan-1,2-diyl, propan-1,1,-diyl,propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl, butan-1,3-diyl,butan-1,2-diyl, 2-methyl-propan-1,3-diyl, and the like. In someembodiments, the alkylene moiety contains 2 to 6, 2 to 4, 2 to 3, 1 to6, 1 to 4, or 1 to 2 carbon atoms.

As used herein, the term “C_(n-m) alkoxy”, employed alone or incombination with other terms, refers to a group of formula —O-alkyl,wherein the alkyl group has n to m carbons. Example alkoxy groupsinclude, but are not limited to, methoxy, ethoxy, propoxy (e.g.,n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), andthe like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1to 3 carbon atoms.

As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments, ahalo is F, Cl, or Br. In other embodiments, halo is F, Cl, or I. Inother embodiments, halo is F, I, or Br.

As used herein, the term “C_(n-m) haloalkyl”, employed alone or incombination with other terms, refers to an alkyl group having from onehalogen atom to 2s+1 halogen atoms which may be the same or different,where “s” is the number of carbon atoms in the alkyl group, wherein thealkyl group has n to m carbon atoms. In some embodiments, the haloalkylgroup is fluorinated only. In some embodiments, the alkyl group has 1 to6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, “C_(n-m) haloalkoxy” refers to a group of formula—O-haloalkyl having n to m carbon atoms. An example haloalkoxy group isOCF₃. In some embodiments, the haloalkoxy group is fluorinated only. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “amino” refers to a group of formula —NH₂.

As used herein, the term “C_(n-m) alkylamino” refers to a group offormula —NH(alkyl), wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms. Examples of alkylamino groups include, but are not limited to,N-methylamino, N-ethylamino, N-propylamino (e.g., N-(n-propyl)amino andN-isopropylamino), N-butylamino (e.g., N-(n-butyl)amino andN-(tert-butyl)amino), and the like.

As used herein, the term “di C_(n-m) alkylamino” refers to a group offormula —N(alkyl)₂, wherein each alkyl group independently has n to mcarbon atoms. In some embodiments, each alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms. Examples of dialkylamino groups include, but arenot limited to, N,N-methylehtylamino, N,N-diethylamino,N,N-propylethylamino, N,N-butylisopropylamino, and the like.

As used herein, the term “C_(n-m) alkoxycarbonyl” refers to a group offormula —C(O)O— alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms. Examples of alkoxycarbonyl groups include, but are notlimited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl (e.g.,n-propoxycarbonyl and isopropoxycarbonyl), butoxycarbonyl (e.g.,n-butoxycarbonyl and tert-butoxycarbonyl), and the like.

As used herein, the term “C_(n-m) alkylcarbonyl” refers to a group offormula —C(O)-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms. Examples of alkylcarbonyl groups include, but are not limited to,methylcarbonyl, ethylcarbonyl, propylcarbonyl (e.g., n-propylcarbonyland isopropylcarbonyl), butylcarbonyl (e.g., n-butylcarbonyl andtert-butylcarbonyl), and the like.

As used herein, the term “C_(n-m) alkylcarbonylamino” refers to a groupof formula —NHC(O)-alkyl, wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “C_(n-m) alkylsulfonylamino” refers to a groupof formula —NHS(O)₂-alkyl, wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “aminosulfonyl” refers to a group of formula—S(O)₂NH₂.

As used herein, the term “C_(n-m) alkylaminosulfonyl” refers to a groupof formula —S(O)₂NH(alkyl), wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminosulfonyl” refers to agroup of formula —S(O)₂N(alkyl)₂, wherein each alkyl group independentlyhas n to m carbon atoms. In some embodiments, each alkyl group has,independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminosulfonylamino” refers to a group offormula —NHS(O)₂NH₂.

As used herein, the term “C_(n-m) alkylaminosulfonylamino” refers to agroup of formula —NHS(O)₂NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminosulfonylamino” refers toa group of formula —NHS(O)₂N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms. In some embodiments, each alkylgroup has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminocarbonylamino”, employed alone or incombination with other terms, refers to a group of formula —NHC(O)NH₂.

As used herein, the term “C_(n-m) alkylaminocarbonylamino” refers to agroup of formula —NHC(O)NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminocarbonylamino” refers toa group of formula —NHC(O)N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms. In some embodiments, each alkylgroup has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylcarbamyl” refers to a group offormula —C(O)—NH(alkyl), wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “di C_(n-m) alkylcarbamyl” refers to a group offormula —C(O)—N(alkyl)₂, wherein each alkyl group independently has n tom carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “carbamyl” to a group of formula —C(O)NH₂.

As used herein, the term “carbonyl”, employed alone or in combinationwith other terms, refers to a —C(═O)— group, which may also be writtenas C(O).

As used herein, the term “carboxy” refers to a —C(O)OH group.

As used herein, the term “cyano-C₁₋₃ alkyl” refers to a group of formula—(C₁₋₃ alkylene)-CN.

As used herein, the term “HO—C₁₋₃ alkyl” refers to a group of formula—(C₁₋₃ alkylene)-OH.

As used herein, the term “thio” refers to a group of formula —SH.

As used herein, the term “C_(n-m) alkylthio” refers to a group offormula —S-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkylsulfinyl” refers to a group offormula —S(O)-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkylsulfonyl” refers to a group offormula —S(O)₂-alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “cyano” refers to a group of formula —CN.

As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbonsincluding cyclized alkyl and/or alkenyl groups. Cycloalkyl groups caninclude mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groupsand spirocycles. Ring-forming carbon atoms of a cycloalkyl group can beoptionally substituted by oxo or sulfido (e.g., C(O) or C(S)). Alsoincluded in the definition of cycloalkyl are moieties that have one ormore aromatic rings fused (i.e., having a bond in common with) to thecycloalkyl ring, for example, benzo or thienyl derivatives ofcyclopentane, cyclohexane, and the like. A cycloalkyl group containing afused aromatic ring can be attached through any ring-forming atomincluding a ring-forming atom of the fused aromatic ring. Cycloalkylgroups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (C₃₋₁₀).

In some embodiments, the cycloalkyl is a C₃₋₁₀ monocyclic or bicycliccyclocalkyl. In some embodiments, the cycloalkyl is a C₃₋₇ monocycliccyclocalkyl. Example cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl,cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, andthe like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

As used herein, “heteroaryl” refers to a monocyclic or polycyclicaromatic heterocycle having at least one heteroatom ring member selectedfrom sulfur, oxygen, and nitrogen. In some embodiments, the heteroarylring has 1, 2, 3, or 4 heteroatom ring members independently selectedfrom nitrogen, sulfur and oxygen. In some embodiments, any ring-formingN in a heteroaryl moiety can be an N-oxide. In some embodiments, theheteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having1, 2, 3 or 4 heteroatom ring members independently selected fromnitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a5-6 monocyclic heteroaryl having 1 or 2 heteroatom ring membersindependently selected from nitrogen, sulfur and oxygen. In someembodiments, the heteroaryl is a five-membered or six-memberedheteroaryl ring. A five-membered heteroaryl ring is a heteroaryl with aring having five ring atoms wherein one or more (e.g., 1, 2, or 3) ringatoms are independently selected from N, O, and S. Exemplaryfive-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl,thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl,1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl,1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. A six-membered heteroarylring is a heteroaryl with a ring having six ring atoms wherein one ormore (e.g., 1, 2, or 3) ring atoms are independently selected from N, O,and S. Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl,pyrimidinyl, triazinyl and pyridazinyl.

As used herein, “heterocycloalkyl” refers to non-aromatic monocyclic orpolycyclic heterocycles having one or more ring-forming heteroatomsselected from O, N, or S. Included in heterocycloalkyl are monocyclic4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl groups.Heterocycloalkyl groups can also include spirocycles. Exampleheterocycloalkyl groups include pyrrolidin-2-one,1,3-isoxazolidin-2-one, pyranyl, tetrahydropuran, oxetanyl, azetidinyl,morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl,tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl,isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl,imidazolidinyl, azepanyl, benzazapene, and the like. Ring-forming carbonatoms and heteroatoms of a heterocycloalkyl group can be optionallysubstituted by oxo or sulfido (e.g., C(O), S(O), C(S), or S(O)₂, etc.).The heterocycloalkyl group can be attached through a ring-forming carbonatom or a ring-forming heteroatom. In some embodiments, theheterocycloalkyl group contains 0 to 3 double bonds. In someembodiments, the heterocycloalkyl group contains 0 to 2 double bonds.Also included in the definition of heterocycloalkyl are moieties thathave one or more aromatic rings fused (i.e., having a bond in commonwith) to the cycloalkyl ring, for example, benzo or thienyl derivativesof piperidine, morpholine, azepine, etc. A heterocycloalkyl groupcontaining a fused aromatic ring can be attached through anyring-forming atom including a ring-forming atom of the fused aromaticring. In some embodiments, the heterocycloalkyl is a monocyclic 4-6membered heterocycloalkyl having 1 or 2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur and having one or moreoxidized ring members. In some embodiments, the heterocycloalkyl is amonocyclic or bicyclic 4-10 membered heterocycloalkyl having 1, 2, 3, or4 heteroatoms independently selected from nitrogen, oxygen, or sulfurand having one or more oxidized ring members.

At certain places, the definitions or embodiments refer to specificrings (e.g., a triazole ring, etc.). Unless otherwise indicated, theserings can be attached to any ring member provided that the valency ofthe atom is not exceeded. For example, a triazole ring may be attachedat any position of the ring, whereas a triazol-1-yl ring is attached atthe 1-position.

As used herein, the term “oxo” refers to an oxygen atom as a divalentsubstituent, forming a carbonyl group when attached to a carbon (e.g.,C═O), or attached to a heteroatom forming a sulfoxide or sulfone group.

As used herein, the term “compound” as used herein is meant to includeall stereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified.

As used herein, the term “tautomer” refers to compounds which arecapable of existing in a state of equilibrium between two isomericforms. Such compounds may differ in the bond connecting two atoms orgroups and the position of these atoms or groups in the compound.

As used herein, the term “isomer” refers to structural, geometric andstereo isomers. As the compound of the present application may have oneor more chiral centers, it is capable of existing in enantiomeric forms.

As used herein, the term “substantially isolated” refers to the compoundthat is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds providedherein. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds provided herein, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, the term “cell” is meant to refer to a cell that is invitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can bepart of a tissue sample excised from an organism such as a mammal. Insome embodiments, an in vitro cell can be a cell in a cell culture. Insome embodiments, an in vivo cell is a cell living in an organism suchas a mammal.

The expressions, “ambient temperature” and “room temperature” or “rt” asused herein, are understood in the art, and refer generally to atemperature, e.g. a reaction temperature, that is about the temperatureof the room in which the reaction is carried out, for example, atemperature from about 20° C. to about 30° C.

As used herein, the term “individual”, “patient”, or “subject” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “effective amount” or “therapeuticallyeffective amount” refers to the amount of active compound orpharmaceutical agent that elicits the biological or medicinal responsein a tissue, system, animal, individual or human that is being sought bya researcher, veterinarian, medical doctor or other clinician.

As used herein the term “treating” or “treatment” refers to 1)preventing the disease; for example, preventing a disease, condition ordisorder in an individual who may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease; 1) inhibiting the disease;for example, inhibiting a disease, condition or disorder in anindividual who is experiencing or displaying the pathology orsymptomatology of the disease, condition or disorder (i.e., arrestingfurther development of the pathology and/or symptomatology), or 2)ameliorating the disease; for example, ameliorating a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,reversing the pathology and/or symptomatology).

As used herein, the tern “ionophore” refers to a molecule thattransports ions across a cell membrane. In some embodiments, ionophoreis a carrier ionophore (i.e., binds to a particular ion to shield itscharge from the surrounding environment and transports an ion throughthe lipid bilayer of a cell membrane).

As used herein, the term “metal chelator” refers to compounds having twoor more donor atoms capable of binding to a metal atom, preferably Cu,Zn or Fe wherein at least two of the donor atoms are capable ofsimultaneous binding to the metal atom and the resultant metal complexhas a thermodynamic stability greater than or equal to that of the metalion: biological ligand complex.

As used herein, the term “pharmaceutical carrier”, or “pharmaceuticallyacceptable carrier” refers to a pharmaceutically acceptable solvent,suspending agent or vehicle for delivering the compound of the presentapplication to the subject. The carrier may be liquid or solid and isselected with the planned manner of administration in mind. Each carriermust be pharmaceutically “acceptable” in the sense of being compatiblewith other ingredients of the composition and non injurious to thesubject.

As used herein, the term “radioisotope” refers to an atom having anatomic mass or mass number different from the atomic mass or mass numbertypically found in nature (i.e., naturally occurring).

As used herein, the term “isotopically” or “radio-labeled” compoundrefers to a compound where one or more atoms are replaced or substitutedby an atom having an atomic mass or mass number different from theatomic mass or mass number typically found in nature (i.e., naturallyoccurring). Example radioisotopes include, but are not limited to, ¹¹C,¹³N, ¹⁵O, ¹⁸F, ^(34m)Cl, ³⁸K, ⁴⁵Ti, ⁵¹Mn, ^(52m)Mn, ⁵²Fe, ⁵⁵Co, ⁶⁰Cu,⁶¹Cu, ⁶²Cu, ⁶⁴Cu, ⁶⁶Ga, ⁶⁷Ga, ⁶⁸Ga, ⁷¹As, ⁷²As, ⁷⁴As, ⁷⁵Br, ⁷⁶Br, ⁸²Rb,⁸⁶Y, ⁸⁹Zr, ⁹⁰Nb, ^(94m)Tc, ^(99m)Tc, ^(110m)In, ¹¹¹In, ¹¹⁸Sb, ¹²⁰I,¹²¹I, ¹²²I, ¹²³I, ¹²⁴I, ¹²⁴I, ¹³¹I, and ²⁰¹Tl.

As used herein, the term “isotopic enrichment factor” refers to theratio between the isotopic abundance and the natural abundance of aspecified isotope.

Examples

Experimental procedures for compounds of the present application areprovided below.

As depicted in the Examples below, compounds are prepared according tothe following general procedures. It will be appreciated that, althoughthe general methods depict the synthesis of certain compounds providedherein, the following general methods, and other methods known to one ofordinary skill in the art, can be applied to all compounds andsubclasses and species of each of these compounds, as described herein.

Analytical Methods:

Nuclear magnetic resonance (NMR) spectra were recorded using a BrukerAvance DPX-400 spectrometer operating at 400 MHz for ¹H NMR and at 101MHz for ¹³C NMR. Low-resolution mass spectrometry (LRMS) was performedon a Micromass ZQ quadrupole mass spectrometer, and high-resolution massspectrometry (HRMS) was performed at the University of Wollongong,Australia using a Bruker Daltonics BioApex-II 7T FTICR spectrometerequipped with an off-axis analytical electron spray ionisation source.Flash chromatography was performed on a Reveleris® Flash ChromatographySystem (Grace Davison Discovery Sciences, Rowville, Australia), fittedwith an ELSD (isopropanol support) and dual-wavelength UV (254 and 280nm) detectors; solvent systems are described where appropriate. HPLCpurity analysis was performed using a Waters Empower 2 system with aWaters 600 pump, Waters in-line degasser AF, Waters temperature controlmodule II, Waters 717 autosampler and Water 2996 PDA. Either an AlltechAlltima C18 (150×4.6 mm, 5 μm pore size) or Waters XTerraRP (150×4.6 mm,5 μm pore size) analytical column was used, with absorbance measured at254 nm. Samples were prepared as 1 mg/mL, with a 10 μL injection.Solvent conditions were as follows:

% C % A (100 mM Flow (MeCN or % B NH₄HCO₃ Entry Time (mL/min) MeOH)(H₂O) pH 8 or 1% TFA) 1 0 1.00 10 80 10 2 20 1.00 90 0 10 3 21 1.00 1080 10

Percentage purity was calculated from the peak area under using Empowersoftware (Waters).

Materials:

5-Fluoro-8-hydroxyquinoline was purchased from Fluorochem.7-Fluoro-8-hydroxyquinoline was purchased from CHEMOS.N-Chlorosuccinimide, N-Bromosuccinimide, N Iodosuccinimide, aluminumtrichloride and trifluoroacetic acid were purchased from Sigma Aldrich.Deuterated solvents were purchased from Cambridge Isotope Laboratories(Novachem, Collingwood, Australia). All commercial materials were usedas received. Unless otherwise stated all solvents used were HPLC gradeor were dried using the MBraun MB SPS-800 solvent purification system.

Examples 1-9 (Compounds 2-10)

Examples 1-9 can be readily prepared according to numerous methods andprocedures available to one of ordinary skill in the art. Such methodsand procedures can be found, for example, in Smith et al., March'sAdvanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6thEd. (Wiley, 2007). Suitable starting materials and intermediates arereadily available from various commercial sources.

Example 10 (Compound 12) 5-chloro-7-fluoro-8-hydroxyquinoline

N-Chlorosuccinimide (120 mg, 0.90 mmol) was added to a solution of7-fluoro-8-hydroxyquinoline (120 mg, 0.74 mmol) in DCM (5 mL). Thereaction mixture was stirred and heated to 40° C. for 5 h and thencooled to rt for 2 days. The reaction was then diluted with DCM (50 ml)and washed with 15% sodium thiosulfate solution (3×10 mL). The organiclayer was dried (Na₂SO₄) and solvent evaporated to give a brown solid.Chromatography of the residue (0→20% EtOAc/hexanes gradient) gave 52 mgof the title product. Yield: 36%. White solid. ¹H NMR (400 MHz, CDCl₃):δ 8.86 (dd, J=1.2, 4.2 Hz, 1H), 8.51 (dd, J=1.6, 8.9 Hz, 1H), 7.54 (dd,J=4.4, 8.9 Hz, 1H), 7.51 (d, J=10.5 Hz, 1H) ppm. ¹³C NMR (400 MHz,CDCl₃): δ 149.50, 146.6 (d, J=246.5 Hz), 139.6 (d, J=7.9 Hz), 137.7 (d,J=10.4 Hz), 133.5 (d, J=2.3 Hz), 123.3, 121.8 (d, J=3.1 Hz), 120.5 (d,J=10.1 Hz), 118.7 (d, J=24.5 Hz) ppm. LRMS (ESI) calcd. for C₉H₆ClFNO[M+H]⁺ 198.01, found 198.10. HRMS (ESI) calcd. C₉H₆ClFNO [M+H]⁺198.0122, found 198.0120. HPLC purity (MeCN/H₂O/0.1% TFA): 99.8%, 7.5min; HPLC purity (MeOH/H₂O/0.1% TFA): 99.6%, 10.4 min.

Example 11 (Compound 13) 5-bromo-7-fluoro-8-hydroxyquinoline

N-Bromosuccinimide (130 mg, 0.73 mmol) was added to a solution of7-fluoro-8-hydroxyquinoline (98 mg, 0.60 mmol) in chloroform (5 mL). Thereaction mixture was stirred and heated to 40° C. overnight and thendiluted with DCM (50 ml) and washed with 15% sodium thiosulfate solution(3×10 mL). The organic layer was dried (Na₂SO₄) and solvent evaporatedto give a brown solid. Chromatography of the residue (0→25%EtOAc/hexanes gradient) gave 60 mg of the title product. Yield: 41%.Pale yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 8.83 (dd, J=1.3, 4.3 Hz,1H), 8.46 (dd, J=1.5, 8.6 Hz, 1H), 7.71 (d, J=10.3 Hz, 1H), 7.54 (dd,J=4.3, 8.6 Hz, 1H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ 149.3, 146.7 (d,J=248.0 Hz), 139.7 (d, J=7.6 Hz), 138.2 (d, J=10.5 Hz), 135.9 (d, J=2.0Hz), 124.4, 122.1, 121.9 (d, J=20.1 Hz), 109.3 (d, J=9.8 Hz) ppm. LRMS(ESI) cacld. C₉H₆BrFNO [M+H]⁺ 241.96, found 242.10. HRMS (ESI) C₉H₆BrFNOcalcd. [M+H]⁺ 241.9617, found 241.9615. HPLC purity (MeCN/H₂O/0.1% TFA):97.9%, 9.9 min; HPLC purity (MeOH/H₂O/0.1% TFA): 98.6%, 17.8 min.

Example 12 (Compound 14) 7-fluoro-5-iodo-8-hydroxyquinoline

N-iodosuccinimide (166 mg, 0.74 mmol) was added to a solution of7-fluoro-8-hydroxyquinoline (100 mg, 0.61 mmol) in chloroform (10 mL).The reaction mixture was stirred and heated to reflux overnight and thendiluted with DCM (50 ml) and washed with 15% sodium thiosulfate solution(3×10 mL). The organic layer was dried (Na₂SO₄) and solvent evaporatedto give a brown solid. Chromatography of the residue (0→20%EtOAc/hexanes gradient) gave 93 mg of the title product. Yield: 53%.Pale yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 8.77 (dd, J=1.3, 4.2 Hz,1H), 8.30 (dd, J=1.4, 8.6 Hz, 1H), 7.95 (d, J=10.1 Hz, 1H), 7.51 (dd,J=4.2, 8.6 Hz, 1H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ 149.2, 147.2 (d,J=246.6 Hz), 145.9, 140.4 (d, J=2.0 Hz), 139.5 (d, J=7.4 Hz), 139.1 (d,J=10.2 Hz), 128.7 (d, J=23.9 Hz), 126.9 (d, J=1.4 Hz), 122.5 (d, J=2.5Hz), 82.7 (d, J=8.8 Hz) ppm. LRMS (ESI) cacld. C₉H₆FINO [M+H]⁺ 289.95,found 289.58. HRMS (ESI) cacld. C₉H₆FINO [M+H]⁺ 289.9478, found289.9476. HPLC purity (MeCN/H₂O/0.1% TFA): 96.8%, 8.8 min; HPLC purity(MeOH/H₂O/0.1% TFA): 96.5%, 12.1 min.

Example 13 (Compound 15) 7-chloro-5-fluoro-8-hydroxyquinoline

N-Chlorosuccinimide (440 mg, 3.1 mmol) and aluminum trichloride (35 mg,0.26 mmol) was added to a solution of 5-fluoro-8-hydroxyquinoline (424mg, 2.6 mmol) in DCM (10 mL). The reaction mixture was stirred andheated to reflux overnight and then diluted with DCM (50 ml) and washedwith 15% sodium thiosulfate solution (3×10 mL). The organic layer wasdried (Na₂SO₄) and solvent evaporated to give a brown solid.Chromatography of the residue (0→20% EtOAc/hexanes gradient) gave 122 mgof the title product. Yield: 24%. Light brown solid. ¹H NMR (400 MHz,CDCl₃): δ 8.86 (dd, J=1.4, 4.2 Hz, 1H), 8.39 (dd, J=5.0, 8.4 Hz, 1H),7.52 (dd, J=5.0, 8.4 Hz, 1H), 7.23 (d, J=9.7 Hz, 1H) ppm. ¹³C NMR (101MHz, CDCl₃): δ 150.2 (d, J=249.3 Hz), 149.8, 145.1 (d, J=4.4 Hz), 137.9(d, J=4.4 Hz), 130.2 (d, J=2.3 Hz), 122.0 (d, J=2.8 Hz), 118.0 (d,J=19.1 Hz), 114.4 (d, J=10.9 Hz), 112.8 (d, J=23.0 Hz) ppm. LRMS calcd.for C₉H₆ClFNO [M+H]⁺ 198.01, found 197.83. HRMS (ESI) calcd. forC₉H₆ClFNO [M+H]⁺ 198.0122, found 198.0120. HPLC purity (MeCN/H₂O/0.1%TFA): 98.5%, 9.8 min; HPLC purity (MeOH/H₂O/0.1% TFA): 99.4%, 12.4 min.

Example 14 (Compound 16) 7-bromo-5-fluoro-8-hydroxyquinoline

N-Bromosuccinimide (1.26 g, 7.1 mmol) was added to a solution of5-fluoro-8-hydroxyquinoline (970 mg, 5.9 mmol) in chloroform (50 mL).The reaction mixture was stirred and heated to 40° C. overnight and thendiluted with DCM (100 ml) and washed with 15% sodium thiosulfatesolution (3×20 mL). The organic layer was dried (Na₂SO₄) and solventevaporated to give a brown solid. Chromatography of the residue (0→25%EtOAc/hexanes gradient) gave 426 mg of the title product. Yield: 30%.White solid. ¹H NMR (400 MHz, CDCl₃): δ 8.85 (dd, J=1.3, 4.2 Hz, 1H),8.38 (dd, J=1.5, 8.4 Hz, 1H), 7.54 (dd, J=4.3, 8.4 Hz, 1H), 7.37 (d,J=9.4 Hz, 1H) ppm. ¹³C NMR 101 MHz, CDCl₃): δ 150.2 (d, J=251.8 Hz),149.6, 146.4 (d, J=4.4 Hz), 137.6 (d, J=3.9 Hz), 130.2 (d, J=2.9 Hz),122.0 (d, J=2.3 Hz), 118.3 (d, J=19.0 Hz), 101.9 (d, J=10.3 Hz) ppm.LRMS (ESI) calcd. for C₉H₆BrFNO [M+H]⁺ 241.96, found 241.72. HRMS (ESI)calcd. for C₉H₆BrFNO [M+H]⁺ 241.9617, found 241.9621. HPLC purity(MeCN/H₂O/0.1% TFA): 96.5%, 11.6 min; HPLC purity (MeOH/H₂O/0.1% TFA):96.6%, 14.7 min.

Example 15 (Compound 17) 5-fluoro-7-iodo-8-hydroxyquinoline

N-iodosuccinimide (166 mg, 0.74 mmol) was added to a solution of5-fluoro-8-hydroxyquinoline (100 mg, 0.61 mmol) in chloroform (5 mL).The reaction mixture was stirred and heated to 50° C. overnight and thendiluted with DCM (50 ml) and washed with 15% sodium thiosulfate solution(3×10 mL). The organic layer was dried (Na₂SO₄) and solvent evaporatedto give a brown solid. Chromatography of the residue (0→20%EtOAc/hexanes gradient) gave 85 mg of the title product. Yield: 48%. Offwhite needles. ¹H NMR (400 MHz, CDCl₃): δ 8.82 (dd, J=1.7, 4.4 Hz, 1H),8.37 (dd, J=8.4, 1.6 Hz, 1H), 7.54 (dd, J=8.4, 4.3 Hz, 1H), 7.51 (d,J=9.3 Hz, 1H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ 150.2 (d, J=251.2 Hz),149.6 (d, J=3.8 Hz), 149.4, 136.5 (d, J=3.7 Hz), 130.3 (d, J=2.9 Hz),122.2 (d, J=2.2 Hz), 119.6 (d, J=23.0 Hz), 118.9 (d, J=18.7 Hz), 73.7(d, J=9.0 Hz) ppm. LRMS (ESI) calcd. for C₉H₆FINO [M+H]⁺ 289.95, found289.66. HRMS (ESI) calcd. for C₉H₆FINO [M+H]⁺ 289.9478, found 289.9486.HPLC purity (MeCN/H₂O/0.1% TFA): 95.9%, 13.8 min; HPLC purity(MeOH/H₂O/0.1% TFA): 96.1%, 17.0 min.

Example 16 (Compound 23)5,7-dichloro-2-((2-fluoroethoxy)methyl)quinolin-8-ol

Step 1. tert-butyl (5,7-dichloro-2-methylquinolin-8-yl) carbonate

A mixture of 5,7-dichloro-2-methylquinolin-8-ol (10.0 g, 43.8 mmol),Boc₂O (19.1 g, 2.0 equiv.), Et₃N (9.14 mL, 1.5 equiv.) and DMAP (107 mg,0.02 equiv.) in THE (50 mL) was heated with stirring to 80° C. for 12 hunder Argon. The mixture was then cooled to room temperature, andconcentrated in vacuo. The crude was washed with water to yield thedesired product (13.0 g, 39.6 mmol) as a white solid in 90% yield andused in the subsequent step without further purification.

Step 2. tert-butyl (5,7-dichloro-2-formylquinolin-8-yl) carbonate

A mixture of tert-butyl (5,7-dichloro-2-methylquinolin-8-yl) carbonate(12 g, 36.6 mmol), SeO₂ (8.1 g, 2.0 equiv.) in 1,4-dioxane (30 mL) washeated with stirring to 80° C. for 12 h. The progress of the reactionwas monitored by NMR (SeO₂ was needed to be filtered off from NMRsample). When the reaction was complete, the mixture was filtered over aprepacked short column (1 inch silica and 1 inch celite) by reducedpressure using 500 mL DCM. It was known that tert-butyl(5,7-dichloro-2-formylquinolin-8-yl) carbonate was not stable onprolonged silica contact. The filtrate was concentrated and dried overhigh-vac to get yellow solid and used in the next step without furtherpurification.

Step 3. 5,7-dichloro-2-(hydroxymethyl)quinolin-8-ol

A mixture of tert-butyl (5,7-dichloro-2-formylquinolin-8-yl) carbonate(1.0 g, 2.9 mmol), NaBH₄ (332 mg, 3 equiv.) in ethanol (30 mL) wasreacted at r.t. for 12 h. Saturated solution of ammonium chloride (15mL) was added to quench the reaction. Water (50 mL) was then added andthe mixture was extracted with DCM (3×30 mL). The combined extracts werewashed with brine, dried with sodium sulfate, and purified by flashcolumn chromatography (20% EtOAc in Hexanes) on silica to afforded awhite solid, which was then dissolved in the mixture of DCM (10 mL) andTFA (2.5 mL), stirred for 2 h until reaction was complete. SaturateNaHCO₃ solution (20 mL) was then added slowly until the precipitateformed. The precipitate was filtered, washed with water and dried toyield the desired product (570 mg, 80%) as a white solid and thisproduct was used in the next step without further purification.

Step 4. 5,7-dichloro-2-((2-fluoroethoxy)methyl)quinolin-8-ol

A mixture of 5,7-dichloro-2-(hydroxymethyl)quinolin-8-ol (200 mg, 819μmol) and NaH (131 mg, 4.0 equiv.) in DMF (3 mL) was stirred at r.t. for30 min. Then the fluoroethyl tosylate (1.0 equiv.) in DMF (2 mL)solution was added slowly into the mixture and the resultant mixture wasstirred for another 3 h. The progress of the reaction was monitored byTLC. When the reaction was complete, saturated solution of ammoniumchloride (5 mL) was added to quench the unreacted NaH. Water (20 mL) wasthen added and the mixture was extracted with DCM (3×10 mL). Thecombined extracts were washed with brine, dried with sodium sulfate, andpurified by flash column chromatography (EtOAc) on silica to afford5,7-dichloro-2-((2-fluoroethoxy)methyl)quinolin-8-ol (38 mg, 16%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.53 (d, J=8.7 Hz, 1H), 7.81(d, J=11.1 Hz, 2H), 4.88 (s, 2H), 4.71-4.67 (m, 1H), 4.59-4.55 (m, 1H),3.91-3.85 (m, 1H), 3.82-3.76 (m, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ158.92, 148.74, 138.19, 133.70, 127.49, 124.06, 121.22, 119.13, 115.86,83.82, 82.18, 73.12, 69.93, 69.74.

Example 17 (Compound 24)5,7-dichloro-2-((4-fluorobutoxy)methyl)quinolin-8-ol

The title compound was prepared using procedures analogous to thosedescribed for Example 23 using fluorobutyl tosylate to replacefluoroethyl tosylate in Step 4 as white solid (45 mg, 18%). ¹H NMR (400MHz, DMSO-d₆) δ 8.53 (d, J=8.7 Hz, 1H), 7.79 (s, 1H), 7.48 (d, J=7.9 Hz,1H), 4.80 (s, 2H), 3.68 (t, J=6.5 Hz, 2H), 3.59 (t, J=6.2 Hz, 3H), 1.83(d, J=7.3 Hz, 2H), 1.76-1.69 (m, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ148.71, 138.17, 133.63, 128.05, 127.41, 125.48, 121.18, 119.12, 115.80,72.96, 69.70, 45.28, 44.61, 29.42, 29.04, 26.59.

Example 18 (Compound 28)5,7-dichloro-2-((((1-(2-fluoroethyl)-1H-1,2,3-triazol-4-yl)methyl)(methyl)amino)methyl)quinolin-8-ol

Step 1. (E)-5,7-dichloro-2-((methylimino)methyl)quinolin-8-ol

To a tert-butyl (5,7-dichloro-2-formylquinolin-8-yl) carbonate (Preparedin Example 23; Step 2; 2.0 g, 5.8 mmol) solution in THE (100 mL), themethylamine gas was bubbled slowly for 2 h until the precipitate formed.The formed precipitate was filtered, washed with THE and dried to yieldthe desired product (1.5 g, 5.8 mmol) as a white yellow solid in 99%yield which was used in the next step without further purification.

Step 2. 5,7-dichloro-2-((methylamino)methyl)quinolin-8-ol

A mixture of (E)-5,7-dichloro-2-((methylimino)methyl)quinolin-8-ol (1.5g, 5.8 mmol), NaBH₄ (1.1 g, 5 equiv.) in ethanol (50 mL) was reacted atr.t. for 12 h. When the reaction was complete, the mixture was adjustedthe pH to 3 with 0.1 N HCl, and then adjusted the pH to 7 with saturatedammonia water until the precipitate formed. The precipitate wasfiltered, washed with water and dried to yield the desired product (870mg, 3.4 mmol) as a gray solid in 58% yield which was used in the nextstep without further purification.

Step 3.5,7-dichloro-2-((methyl(prop-2-yn-1-yl)amino)methyl)quinolin-8-ol

To the mixture DMF (25 mL) solution of5,7-dichloro-2-((methylamino)methyl)quinolin-8-ol (2.0 g, 7.8 mmol) andDIPEA (2.6 mL, 2 equiv.), the 3-bromopropyne (1.7 mL, 2 equiv.) in DMF(5 mL) was added slowly via syringe at 50° C. The mixture was stirred at50° C. for another 5 min until the reaction was complete. Water (100 mL)was then added and the mixture was extracted with DCM (3×100 mL). Thecombined extracts were washed with brine, dried with sodium sulfate, andpurified by rapid filtration over silica pad and recrystallization toafford the desired product (759 mg, 33%) as a gray solid which was usedin the next step without further purification.

Step 4.5,7-dichloro-2-((((1-(2-fluoroethyl)-1H-1,2,3-triazol-4-yl)methy)(methyl)amino)methyl)quinolin-8-ol

A mixture of5,7-dichloro-2-((methyl(prop-2-yn-1-yl)amino)methyl)quinolin-8-ol (147mg, 0.5 mmol), CuSO₄.5H₂O (13 mg, 0.1 equiv.), sodium ascorbate (20 mg,0.2 equiv.), and fluoroethyl azide (2 equiv.) in THF-H₂O (9:1, 2 mL) wasstirred at r.t. for 30 min. Water (5 mL) was then added and the mixturewas extracted with DCM (3×3 mL). The combined extracts were washed withbrine, dried with sodium sulfate, and purified by flash columnchromatography (DCM-MeOH 15:1) on silica to afforded the desired product(86 mg, 45%) as a gray solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.91 (s, 1H),8.56 (d, J=8.1 Hz, 1H), 8.37 (s, 1H), 7.88 (s, 1H), 7.72 (d, J=7.4 Hz,1H), 4.82 (d, J=30.8 Hz, 2H), 4.61 (s, 2H), 4.41 (d, J=5.9 Hz, 2H), 3.32(d, J=6.0 Hz, 1H), 2.93 (s, 3H), 1.97 (s, 1H); ³C NMR (101 MHz, DMSO-d₆)δ 151.49, 148.49, 137.20, 136.20, 134.56, 127.85, 124.18, 122.20,119.16, 115.89, 57.79, 49.86, 47.72, 46.97, 28.89.

Example 19 (Compound 29)5,7-dichloro-2-((((1-(3-fluoropropyl)-1H-1,2,3-triazol-4-yl)methyl)(methyl)amino)methyl)quinolin-8-ol

The title compound was prepared using procedures analogous to thosedescribed for Example 28 using fluoropropyl azide to replace fluoroethylazide in Step 4 as gray solid (97 mg, 49%). ¹H NMR (400 MHz, DMSO-d₆) δ10.95 (s, 1H), 8.63 (d, J=8.7 Hz, 1H), 8.42 (s, 1H), 7.95 (s, 1H), 7.79(d, J=8.7 Hz, 1H), 4.89 (d, J=31.4 Hz, 2H), 4.67 (s, 2H), 4.49 (t, J=6.9Hz, 2H), 3.38 (s, 2H), 3.00 (s, 3H), 2.04 (s, 2H); ¹³C NMR (101 MHz,DMSO-d₆) δ 151.48, 148.95, 137.38, 136.18, 134.40, 128.20, 127.63,124.05, 122.09, 119.04, 115.88, 57.70, 49.82, 47.73, 46.96, 41.00,40.88.

Example 20 (Compound 30)5,7-dichloro-2-((((1-(4-fluorobutyl)-1H-1,2,3-triazol-4-yl)methyl)(methyl)amino)methyl)quinolin-8-ol

The title compound was prepared using procedures analogous to thosedescribed for Example 28 using fluorobutyl azide to replace fluoroethylazide in Step 4 as gray solid (80 mg, 39%). ¹H NMR (400 MHz, DMSO-d₆) δ10.86 (s, 1H), 8.57 (d, J=8.8 Hz, 1H), 8.35 (d, J=8.9 Hz, 1H), 7.88 (d,J=17.4 Hz, 1H), 7.76-7.68 (m, 1H), 4.82 (d, J=29.6 Hz, 2H), 4.62 (s,2H), 4.39 (t, J=6.8 Hz, 2H), 3.28 (s, 3H), 2.94 (d, J=8.8 Hz, 3H), 1.76(dd, J=15.4, 7.7 Hz, 2H), 1.50-1.38 (m, 1H); ¹³C NMR (101 MHz, DMSO-d₆)δ 148.84, 141.64, 137.41, 134.39, 128.28, 127.37, 124.03, 121.95,119.03, 116.92, 115.83, 57.81, 49.96, 49.00, 26.88, 25.19.

Example A: Ionophore Activity of Synthesized Compounds

Ionophore Assay:

SH-SY5Y cells (American Type Culture Collection, CRL-2266), werecultured in DMEM containing Glutamax (Invitrogen) supplemented with 1 mMsodium pyruvate (Sigma) and 10% fetal calf serum (Sigma). Cells weremaintained at 37° C. with 5% CO₂ and passaged every 3-4 days. Compounds(10 mM) were solubilized in DMSO (Sigma). CQ and PBT2 were used aspositive controls. Cells were treated with growth media supplementedwith each compound (20 M) or vehicle for 6 hours. Cells were harvestedand metal levels were measured with Inductively-Coupled Plasma MassSpectrometry (Varian), as previously described. (See, e.g., Cherny, R.A. et al., (2001) Treatment with a copper-zinc chelator markedly andrapidly inhibits beta-amyloid accumulation in Alzheimer's diseasetransgenic mice, Neuron 30, 665) K was used as an internal standard andCu, Zn and Fe levels expressed relative to vehicle treated controlcells. Data represents the mean and S.E.M. of at least 9 replicates from3 experiments. A oneway ANVOA with Fisher's LSD test was used todetermine statistical differences relative to control (Prism 6,Graphpad).

FIG. 1 describes ionophore assay of 8HQ derivatives (8HQ and compounds2-10). Dashed line indicates control level. SH-SY5Y cells treated weretreated with each compound (20 μM) for 6 hours and cellular metal levelswere measured with ICP-MS.

FIG. 2 describes ionophore activity of CQ derivatives (CQ and compounds12-17). SH-SY5Y cells treated were treated with each compound (20 μM)for 6 hours and cellular metal levels were measured with ICP-MS. Dashedline indicates control level.

FIG. 3 describes ionophore activity of PBT2 derivatives (PBT2 andcompounds 23, 24, 28, 29, 30). SH-SY5Y cells treated were treated witheach compound (20 μM) for 6 hours and cellular metal levels weremeasured with ICP-MS. Dashed line indicates control level.

Example B: Aβ Reversal Assays

Aβ Aggregation Assay:

4,4(′)-dianilino-1,1(′)-binaphthyl-5,5(′)-disulfonate (bis-ANS, Sigma)was used to assess whether compounds could reverse the aggregation ofsoluble A oligomers. (See, e.g., LeVine, H., 3rd, (2002)4,4(′)-Dianilino-1,1(′)-binaphthyl-5,5(′)-disulfonate: report onnon-beta-sheet conformers of Alzheimer's peptide beta(1-40), ArchBiochem Biophys 404, 106; Chen, W. T. et al., (2011) Distinct effects ofZn²⁺, Cu²⁺, Fe³⁺, and Al³⁺ on amyloid-beta stability, oligomerization,and aggregation: amyloid-beta destabilization promotes annularprotofibril formation, J Biol Chem 286, 9646) Human A 1-42 (ChinaPeptide) was dissolved in DMSO (Sigma) to a stock concentration of 1.5mM. A (15 M) oligomers were induced with ZnSO₄ (15 μM) at 26° C. for 30min in a buffer (pH 7.4) containing Tris (50 mM), NaCl (150 mM) andbis-ANS (10 μM). Compounds (0.1 to 120 μM) dissolved in DMSO (Sigma)were added for 30 min. CQ and PBT2 were used as positive controls.Endpoint fluorescence (excitation=390 nm, emission=490 nm) was measuredwith a Flex Station (Molecular Devices) fluorescent plate reader. Ateach concentration, Aβ fluorescence was normalized to backgroundfluorescence and then expressed as a percentage of vehicle treatedcontrol samples. The effective concentration that reversed Aβaggregation by 50% relative to control (EC₅₀) was determined withnon-linear regression analysis (Prism 6, Graphpad). Data represents themean of at least 9 replicates from 3 experiments.

TABLE 1 Reversal of aggregation of soluble Aβ oligomers by fluorinated8-hydroxyquinoline derivatives^(a) Compound No. EC₅₀ (μM) 5 >120 6 43.57 21.5 8 37.5 9 14.0 10 15.4 Clioquinol (CQ) 1.8 12 4.9 13 3.5 14 2.3 155.2 16 3.7 17 2.5 PBT2 2.0 23 2.4 24 2.0 28 2.3 29 4.5 30 2.8^(a)Aggregation of Aβ oligomers was assessed fluorometrically withbis-ANS. EC₅₀ was determined with non-linear regression analysis (Prism6, Graphpad). CQ and PBT2 were used as positive controls. Data representmean of at least three independent experiments.

The compounds of the present application showed superior bindingaffinity, metal selectivity and Cu and Zn ionophore activity over theagents CQ and PBT2.

Evaluation of fluorine substituents around the hydroxyquinoline revealedthat compound 5 and compound 6 were inferior to 8HQ in terms of Cuuptake while compounds 7-9 showed equal or superior Cu uptake (FIG. 1).Neuronal Zn uptake was largely unaffected. Replacement of labile iodineon CQ with other halides, such as fluoride, chloride or bromide, wascarried out at various positions to improve the stability of themolecule due to higher C—X (X═F, Cl or Br) bond energies (Chart 3).Among six analogs screened, compounds 15-17 showed improved ionophoreability of both Cu and Zn (FIG. 2).

Compounds 28-30 showed exceptional Cu uptake (10-fold increase forcompound 28, 16-fold increase for compound 29 and 8-fold increase forcompound 30) than that of PBT2. For Zn neuronal uptake, compounds 28-30showed comparable results as PBT2 (FIG. 3).

Compounds 6-10 showed improved anti A aggregation activities compared tocompound 5. Compounds 12-14 and compounds 15-17 have EC₅₀ values in therange of 2.3-5.2 μM. Compounds 23, 24 and 28-30 (EC₅₀=2.0-4.5 μM) arealso excellent candidates.

It is appreciated that certain features of the disclosure, which are,for clarity, described in the context of separate embodiments, can alsobe provided in combination in a single embodiment. Conversely, variousfeatures of the disclosure which are, for brevity, described in thecontext of a single embodiment, can also be provided separately or inany suitable subcombination.

OTHER EMBODIMENTS

It is to be understood that while the present application has beendescribed in conjunction with the detailed description thereof, theforegoing description is intended to illustrate and not limit the scopeof the present application, which is defined by the scope of theappended claims. Other aspects, advantages, and modifications are withinthe scope of the following claims.

1-195. (canceled)
 196. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: Hal is selectedfrom the group consisting of Cl, F, Br, and I; n is 1, 2, or 3; X isselected from the group consisting of O, S, S(O), S(O)₂, C(O), andNR^(N); L¹ is selected from the group consisting of —C₁₋₆ alkylene-,—Y—C₁₋₆ alkylene-, —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-, and —(O—C₁₋₄alkylene)_(m)-, wherein m is an integer from 1 to 5, and wherein saidalkylene groups are each optionally substituted with 1, 2, or 3substituents independently selected from halo, CN, OH, C₁₋₃ alkyl, C₁₋₃alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, anddi(C₁₋₃ alkyl)amino; L² is selected from the group consisting of —C₁₋₆alkylene-, —C₁₋₆ alkylene-Y—, —C₁₋₄ alkylene-Y—C₁₋₄ alkylene-, and—(C₁₋₄ alkylene-O—)_(m)—, wherein m is an integer from 1 to 5, andwherein said alkylene groups are each optionally substituted with 1, 2,or 3 substituents independently selected from halo, CN, OH, C₁₋₃ alkyl,C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,and di(C₁₋₃ alkyl)amino; each Y is independently selected from the groupconsisting of O, S, S(O), S(O)₂, C(O), C(O)NR^(f), NR^(f)C(O),S(O)₂NR^(f), NR^(f)S(O)₂, and NR^(f); each R^(f) is independentlyselected from the group consisting of H and C₁₋₃ alkyl; R^(N) isselected from the group consisting of H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₄ haloalkyl, C₃₋₁₀ cycloalkyl, and 4-10 memberedheterocycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₄ haloalkyl, C₃₋₁₀ cycloalkyl, and 4-10 membered heterocycloalkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(g) groups; group A is selected from the group consisting of a 5-10membered heteroaryl and 4-10 membered heterocycloalkyl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups; alternatively, group A is H; with the proviso that when X isNR^(N), L¹ is —C₁₋₆ alkylene-, L² is —C₁₋₆ alkylene-, and R^(N) is C₁₋₆alkyl, group A is not H; each R^(A) is independently selected from thegroup consisting of OH, NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₄ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylsulfonylamino,aminosulfonyl, C₁₋₆ alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₆alkylaminocarbonylamino, and di(C₁₋₆ alkyl)aminocarbonylamino; and eachR^(g) is independently selected from the group consisting of OH, NO₂,CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino, C₁₋₆alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino.
 197. The compound of claim 196, wherein thecompound of Formula (I) is a compound of Formula (Ia):

or a pharmaceutically acceptable salt thereof.
 198. The compound ofclaim 196, wherein: Hal is selected from the group consisting of: Cl, F,and I; X is selected from the group consisting of O and NR^(N); L¹ is—C₁₋₆ alkylene-, wherein said alkylene group is optionally substitutedwith 1, 2, or 3 substituents independently selected from halo, CN, OH,C₁₋₃ alkoxy, and amino; L² is —C₁₋₆ alkylene-, wherein said alkylenegroup is optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, CN, OH, C₁₋₃ alkoxy, and amino; R^(N)is selected from the group consisting of H and C₁₋₆ alkyl; group A is 5or 6 membered heteroaryl, which is optionally substituted by 1, 2, or 3independently selected R^(A) groups; alternatively, group A is H; withthe proviso that when X is NR^(N), L¹ is —C₁₋₆ alkylene-, L² is —C₁₋₆alkylene-, and R^(N) is C₁₋₆ alkyl, group A is not H; and each R^(A) isindependently selected from the group consisting of OH, NO₂, CN, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, amino, C₁₋₆alkylamino, and di(C₁₋₆ alkyl)amino.
 199. The compound of claim 196,wherein the compound of Formula (Ia) is a compound of Formula (Ib):

or a pharmaceutically acceptable salt thereof, wherein: Hal is selectedfrom the group consisting of Cl, F, and I; and R⁰ is —C₁₋₆ alkyl, whichis optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, C₁₋₃ alkoxy, amino, C₁₋₃ alkylamino, anddi(C₁₋₃ alkyl)amino.
 200. The compound of claim 196, wherein thecompound of Formula Ia is a compound of Formula Ic:

or a pharmaceutically acceptable salt thereof, wherein: Hal is selectedfrom the group consisting of Cl, F, and I; and group A is selected fromthe group consisting of a 5-6 membered heteroaryl and 4-10 memberedheterocycloalkyl, each of which is optionally substituted by 1, 2, 3, or4 independently selected R^(A) groups.
 201. The compound of claim 196,wherein group A is a triazolyl of Formula A-1c:

wherein R^(A) is selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, cyano-C₁₋₃ alkyl, and HO—C₁₋₃ alkyl.
 202. The compound ofclaim 196, wherein the compound of Formula (I) is selected from thegroup consisting of:

or a pharmaceutically acceptable salt thereof.
 203. The compound ofclaim 196, having formula:

or a pharmaceutically acceptable salt thereof.
 204. The compound ofclaim 196, having formula:

or a pharmaceutically acceptable salt thereof.
 205. The compound ofclaim 196, having formula:

or a pharmaceutically acceptable salt thereof.
 206. The compound ofclaim 196, having formula:

or a pharmaceutically acceptable salt thereof.
 207. The compound ofclaim 196, having formula:

or a pharmaceutically acceptable salt thereof.
 208. A pharmaceuticalcomposition comprising a compound of claim 196, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier.
 209. A method of treating a disease of condition selected froma neurological disorder and a cancer in a subject in need thereof, themethod comprising administering to the subject a therapeuticallyeffective amount of a compound of claim 196, or a pharmaceuticallyacceptable salt thereof.
 210. The method of claim 209, wherein thedisease of condition is a neurological disorder.
 211. The method ofclaim 209, wherein the disease of condition is a neurological disorderselected from the group consisting of Alzheimer's disease (AD),Parkinson's disease (PD), Huntington's Disease (HD), motor neuronedisease (MND), Prion disease, cerebral amyloid angiopathy, vascularcognitive impairment (VCI), dementia, dementia with Lewy bodies,frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS),multiple sclerosis, hippocampal sclerosis, Binswanger's disease, andCreutzfeldt-Jakob disease.
 212. The method of claim 209, wherein thedisease or condition is Alzheimer's disease (AD).
 213. The method ofclaim 209, wherein the disease of condition is a cancer.
 214. The methodof claim 209, wherein the disease of condition is a cancer selected fromthe group consisting of bladder cancer, brain cancer, breast cancer,colorectal cancer, cervical cancer, gastrointestinal cancer,genitourinary cancer, head and neck cancer, lung cancer, ovarian cancer,pancreatic cancer, prostate cancer, renal cancer, skin cancer, andtesticular cancer.
 215. The method of claim 209, wherein the disease orcondition is prostate cancer.